Gene Annotation
Available parameters and response documentation is available here
GET /lookup/gene/TP53/hg19?add-all-data=1&=&format=api
{ "gene_id": 33956, "symbol": "TP53", "description": "tumor protein p53", "synonyms": [ "LFS1", "p53" ], "cgd": { "version": "15-Jan-2024", "pub_med_references": [ 1349175, 1565143, 1565144, 1591732, 1679237, 1978757, 3409256, 6016796, 7887414, 8118819, 8718514, 9242456, 10612830, 11219776, 11332399, 11481490, 11498785, 11600572, 12085209, 12524418, 12610779, 12619118, 14583457, 15381368, 15695383, 15741269, 15977174, 18762572, 19171829, 19556618, 19652052, 20301488, 21056402, 21601526, 21837677, 21946351, 21990040, 22170717, 22551548, 22672556, 22878818, 22939227, 23015295, 23175693, 23355100, 23409989, 23667851, 23894400, 30146126 ], "condition": "Li-Fraumeni syndrome; Choroid plexus papilloma; Ependymoma, intracranial; Osteogenic sarcoma; Breast cancer, familial; Hepatoblastoma; Non-Hodgkin lymphoma; Adrenocortical carcinoma; Colorectal cancer; Bone marrow failure syndrome 5", "inheritance": "AD", "age_group": "Pediatric", "intervention_categories": [ "Oncologic" ], "comments": "Variants may also be involved in susceptibility to a number of types of neoplasms (eg, Basal cell carcinoma, susceptibility to, Glioma, susceptibility to)", "intervention": null }, "civic": { "version": "08-Dec-2023", "items": [ { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Head And Neck Squamous Cell Carcinoma", "doid": "5520", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/517", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In a study of 74 patients with head and neck squamous cell carcinoma, those with disruptive mutations in TP53 had shorter overall survival and a higher rate of locoregional recurrence than those without mutations or with nondisruptive mutations.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 22090360 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "Deleterious Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Head And Neck Squamous Cell Carcinoma", "doid": "5520", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/518", "evidence_direction": "Does Not Support", "evidence_level": "B", "evidence_statement": "Unlike other studies, in this study of 110 patients with head and neck squamous cell carcinoma, there was no significant difference in the overall survival of patients with and without any TP53 mutations.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 8901856 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Esophagus Squamous Cell Carcinoma", "doid": "3748", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/519", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In a retrospective study of patients with esophageal carcinoma, those with mutations in TP53 had worse overall survival.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 19941080 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "B-lymphoblastic Leukemia/lymphoma", "doid": "0080630", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/520", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In children with bone marrow relapsed B-cell precursor acute lymphoblastic leukemia, in multivariate analysis those with mutations in TP53 had worse event-free survival than patients without mutations.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 22699455 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Myelodysplastic Syndrome", "doid": "0050908", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/521", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In patients with myelodysplastic syndrome, in a multivariate analysis those with mutations in TP53 had shorter overall survival than wild-type patients.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 24836762 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Myeloid Neoplasm", "doid": "0070004", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/522", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In patients with myeloma, those with mutations in TP53 had worse overall survival than those without.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 17215851 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Head And Neck Squamous Cell Carcinoma", "doid": "5520", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/523", "evidence_direction": "Does Not Support", "evidence_level": "B", "evidence_statement": "Tumors from 114 patients with head and neck squamous cell carcinoma were analyzed for TP53 mutations, 21 of which were treated with surgery. Unlike those treated with radiotherapy, those treated with surgery did not show a significant difference in rates of loco-regional control between those with and without mutations in TP53.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11325447 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Head And Neck Squamous Cell Carcinoma", "doid": "5520", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/524", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "Tumors from 114 patients with head and neck squamous cell carcinoma were analyzed for TP53 mutations. Of the 93 patients treated with radiotherapy, patients with mutations in TP53 had lower rates of loco-regional control and shorter disease-free, disease-specific, and overall survival.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11325447 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Head And Neck Squamous Cell Carcinoma", "doid": "5520", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/525", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In patients with head and neck squamous cell carcinoma, in a multivariate analysis those with truncating mutations in TP53 had worse progression-free and overall survival than wild-type patients.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 21467160 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "Truncating Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Head And Neck Squamous Cell Carcinoma", "doid": "5520", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/526", "evidence_direction": "Does Not Support", "evidence_level": "B", "evidence_statement": "In patients with head and neck squamous cell carcinoma, when comparing patients with any mutation in TP53 to wild-type, there was not a significant difference in overall survival in a multivariate analysis.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 21467160 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "Truncating Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "B-lymphoblastic Leukemia/lymphoma", "doid": "0080630", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/640", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In relapsed B-ALL patients, TP53 mutations were associated with morphologic nonresponse to therapy (>5% blasts in the bone marrow after 9 weeks of treatment) as well as reduced event free and overall survival when compared to TP53 wildtype patients.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 21747090 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Oral Squamous Cell Carcinoma", "doid": "0050866", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/641", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "Oral squamous cell carcinoma patients with TP53 mutations in the DNA binding domain (L2, L3 and the LSH motif) have significantly reduced cumulative survival when compared to patients with TP53 mutations outside of this DNA binding domain. These mutations were also significantly associated with locoregional failure, cervical lymph node metastasis and distant metastasis, likely contributing to this finding.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 12509970 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "DNA Binding Domain Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Gastric Adenocarcinoma", "doid": "3717", "drug_interaction_type": null, "drugs": [ "Chemotherapy" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/850", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In this meta-analysis of 13 studies (564 patients) p53 positivity as defined by high protein expression and/or p53 mutation was associated with improved response to chemotherapy (risk ratio [RR] = 0.704; 95% confidence intervals [CI] = 0.550-0.903; P = 0.006).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 24740294 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Breast Cancer", "doid": "1612", "drug_interaction_type": null, "drugs": [ "Doxorubicin" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/851", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "In this preclinical study, MMTV-Wnt1 mammary tumors with mutant TP53 showed a better clinical response to chemotherapy (doxorubicin) than TP53 wild-type tumors. This was mediated by wild-type TP53-induced cell-arrest under chemotherapy even in the context of heterozygous TP53 point mutations or absence of p21. Thus the status of both TP53 alleles should be assessed because even one copy of wild-type TP53 may contribute to poor response to chemotherapy.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": [ "Doxorubicin" ], "phenotypes": null, "pub_med_references": [ 22698404 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": null, "drugs": [ "Cetuximab", "Oxaliplatin", "Capecitabine" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/875", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In this retrospective biomarker analysis of the EXPERT-C trial, patients with TP53 wild-type status had a statistically significant better progression free survival (PFS) (89.3% vs 65.0% at 5 years; hazard ratio [HR] = 0.23; 95% confidence interval [CI] = 0.07 to 0.78; two-sided P = .02 by Cox regression) and overall survival (OS) (92.7% vs 67.5% at 5 years; HR = 0.16; 95% CI = 0.04 to 0.70; two-sided P = .02 by Cox regression) when treated with Cetuximab + CAPOX (Capecitabine, Oxaliplatin) than in the control arm without Cetuximab.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:33 UTC", "nct_ids": null, "normalized_drug": [ "Capecitabine, Cetuximab, Oxaliplatin" ], "phenotypes": null, "pub_med_references": [ 24957073 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "Wildtype", "variant_civic_url": null, "variant_origin": null, "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Esophageal Carcinoma", "doid": "1107", "drug_interaction_type": null, "drugs": [ "Chemotherapy" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/906", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "Patients with p53 wild type (as defined by low expression and/or wild-type tp53 gene) had a higher response rate to chemotherapy-based treatment (total major response [MR]: risk ratio [RR] = 1.09, 95 % CI = 1.03-1.16, P = .003; pathological MR: RR = 1.15, 95 % CI = 1.06-1.25, P = .001; total complete response [CR]: RR = 1.08, 95 % CI = 1.00-1.17, P = .040) in this meta-analysis (28 studies, 1497 cases).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:33 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 23515910 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "Wildtype", "variant_civic_url": null, "variant_origin": null, "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Acute Myeloid Leukemia", "doid": "9119", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1018", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In a study of 97 patients with AML treated with HSCT, 40 had TP53 mutations comprising a total of 44 mutations. Patients with a TP53 mutation had a reduced three year probability of overall survival and event-free survival compared to patients with the wild-type TP53.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 26771088 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Adrenocortical Carcinoma", "doid": "3948", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1028", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "TP53 mutation was shown to be associated with shorter overall survival in patients with adrenocortical tumors (log-rank test; P=0.098). Of 20 patients studied, 5 had coding mutation in TP53. Four of the 5 patients with a TP53 mutation had metastases at diagnosis or detected soon thereafter, and 3 of 4 died of disease within 12 months of surgical resection.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 15922892 ], "rating": "2", "representative_transcript": null, "transcripts": null, "variant": "Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Lung Non-small Cell Carcinoma", "doid": "3908", "drug_interaction_type": null, "drugs": [ "Selumetinib", "Docetaxel" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1145", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "A clinical trial comparing selumetinib and docetaxel vs. docetaxel and placebo in KRAS mutant NSCLC was recapitulated in mice. Tumors were induced in lung epithelium by nasal instillation of CRE-bearing adenovirus in conditionally targeted mice. Kras(G12D) and Trp53 knockout mutant mice were resistant to docetaxel monotherapy but sensitive to combined treatment. In a small number of human NSCLC patients with these genotypes FDG-PET signal intensity changes and pERK IHC staining correlated with mouse data.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": [ "Docetaxel, Selumetinib" ], "phenotypes": null, "pub_med_references": [ 22425996 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Lung Non-small Cell Carcinoma", "doid": "3908", "drug_interaction_type": null, "drugs": [ "Docetaxel" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1146", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "A clinical trial comparing selumetinib and docetaxel vs. docetaxel and placebo in KRAS mutant NSCLC was recapitulated in mice. Tumors were induced in lung epithelium by nasal instillation of CRE-bearing adenovirus in conditionally targeted mice. Kras(G12D) and Trp53 knockout mutant mice were resistant to docetaxel monotherapy but sensitive to combined treatment. In a small number of human NSCLC patients with these genotypes FDG-PET signal intensity changes and pERK IHC staining correlated with mouse data.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-05-03 22:19:58 UTC", "nct_ids": null, "normalized_drug": [ "Docetaxel" ], "phenotypes": null, "pub_med_references": [ 22425996 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "Loss", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Lung Non-small Cell Carcinoma", "doid": "3908", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1147", "evidence_direction": "Does Not Support", "evidence_level": "B", "evidence_statement": "Pooled analysis of TP53 mutations (exons 5-8) from 4 randomized trials (IALT, JBR10, CALGB-9633 and ANITA). Mutations (434; 36%) had no prognostic effect (OBS: HROS=0.99; [95%CI 0.77-1.28], p=0.95; HRDFS=0.99 [0.78-1.25], p=0.92) but were marginally predictive of benefit from ACT for OS (test for interaction: OS: p=0.06; DFS: p=0.11).", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 26899019 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "Deleterious Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Lung Non-small Cell Carcinoma", "doid": "3908", "drug_interaction_type": null, "drugs": [ "Adjuvant Chemotherapy" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1148", "evidence_direction": "Does Not Support", "evidence_level": "B", "evidence_statement": "Pooled analysis of TP53 mutations (exons 5-8) from 4 randomized trials (IALT, JBR10, CALGB-9633 and ANITA) of platinum-based adjuvant chemotherapy (ACT) versus observation (OBS). Patients with TP53wt had significantly better PFS and OS with ACT vs. OBS (p=0.005, p=0.02, respectively) whereas patients with TP53 mutations did not show significant differences in PFS and OS between ACT and OBS (p=0.86, p=0.63).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 26899019 ], "rating": "2", "representative_transcript": null, "transcripts": null, "variant": "Deleterious Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Lung Non-small Cell Carcinoma", "doid": "3908", "drug_interaction_type": null, "drugs": [ "Adjuvant Chemotherapy" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1149", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "Pooled analysis of TP53 mutations (exons 5-8) from 4 randomized trials (IALT, JBR10, CALGB-9633 and ANITA, 1209 patients, median follow-up 5.5 years) of platinum-based adjuvant chemotherapy (ACT) versus observation (OBS). Patients with wild-type TP53 had better outcomes with ACT than OBS (HROS=0.77 [0.62-0.95], p=0.02; HRDFS=0.75 [0.62-0.92], p=0.005).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:33 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 26899019 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "Wildtype", "variant_civic_url": null, "variant_origin": null, "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Sarcoma", "doid": "1115", "drug_interaction_type": null, "drugs": [ "Pazopanib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1170", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "19 advanced sarcoma patients treated with pazopanib were retrospectively assessed for mutations associated with response using the Foundation one sarcoma/heme panel. Progression-free survival (PFS) of patients with TP53 mutations (all predicted to be loss of function) was significantly greater than TP53 wild-type tumors with the median PFS of 208 versus 136 days, respectively [P = 0.036, hazards ratio 0.38 (95% confidence interval 0.09-0.83)].", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": [ "Pazopanib" ], "phenotypes": null, "pub_med_references": [ 26646755 ], "rating": "2", "representative_transcript": null, "transcripts": null, "variant": "Deleterious Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Chronic Lymphocytic Leukemia", "doid": "1040", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1450", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "A study of 53 patients with B-CLL found a significant resistance to chemotherapy and corresponding poor clinical outcomes among the 7 treated patients with p53 mutations compared to the 29 treated patients without.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 8241511 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Chronic Lymphocytic Leukemia", "doid": "1040", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1451", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In a study of 126 patients with long-term follow-up, TP53 mutations were significantly associated with shorter median survival in patients (P = 0.002) from time of diagnosis. The median survival from the time of first observation of a TP53 mutation was much more pronounced (P = <0.001). These findings were statistically independent of 17p deletions.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 18689542 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Chronic Lymphocytic Leukemia", "doid": "1040", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1452", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "The authors analyzed 328 patients with CLL, of which 28 were identified to have TP53 mutations. Patients with TP53 mutations were found to have significantly shorter progression-free (HR = 3.8; P < 0.001) and overall survival (HR = 7.2; P < 0.001).", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 20697090 ], "rating": "5", "representative_transcript": null, "transcripts": null, "variant": "Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Chronic Lymphocytic Leukemia", "doid": "1040", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1478", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In the CLL4 trial assessing first line treatment with chlorambucil or fludarabine with or without cyclophosphamide, patients with TP53 mutations experienced poorer overall response rates (27% vs 83%), shorter progression free survival (5 year PFS 5% vs 17%), and overall survival (20% vs 59%) compared to patients without TP53 mutations.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 21483000 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Chronic Lymphocytic Leukemia", "doid": "1040", "drug_interaction_type": null, "drugs": [ "Alemtuzumab" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1481", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "Thirty-six patients with CLL were treated with alemtuzumab. Partial or complete response was achieved in 6 of 15 patients with p53 mutations, compared to 4 of 21 without. These findings are not statistically significant, but the authors suggest that alemtuzumab is an effective therapy for patients with p53 mutations or deletions.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": [ "Alemtuzumab" ], "phenotypes": null, "pub_med_references": [ 14726385 ], "rating": "2", "representative_transcript": null, "transcripts": null, "variant": "Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Chronic Lymphocytic Leukemia", "doid": "1040", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1485", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In a multivariate analysis of 774 CLL patients, TP53 aberrations were significantly correlated with shorter time to first treatment (HR=2.081; 95% CI=1.431-3.021). This finding was independent of IGHV mutation status.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 24943832 ], "rating": "5", "representative_transcript": null, "transcripts": null, "variant": "Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Chronic Lymphocytic Leukemia", "doid": "1040", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1507", "evidence_direction": "Supports", "evidence_level": "A", "evidence_statement": "In a cohort of 406 patients with CLL, those patients with clonal or sub-clonal mutations in TP53 had significantly shorter overall survival (HR: 1.71; 95% CI: 1.28-2.26; P = .0001).", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 26837699 ], "rating": "5", "representative_transcript": null, "transcripts": null, "variant": "Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Ovarian Cancer", "doid": "2394", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2697", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "p53 overexpression (>10% positive stained nuclei) was found in 110 cases from a 178 patient cohort with invasive ovarian carcinoma who had undergone surgery. Overexpression of p53 was correlated with poor differentiation (p<0.001) and high S-phase fraction (p<0.001).", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:44 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11595686 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "Overexpression", "variant_civic_url": null, "variant_origin": null, "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Ovarian Cancer", "doid": "2394", "drug_interaction_type": null, "drugs": [ "Cisplatin", "Carboplatin" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2771", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In a group of patients with invasive ovarian carcinoma who had undergone surgery, a subset of 74 patients treated with platinum based chemotherapy were assessed for p53 alteration (p53 mutation or p53 overexpression by immunostaining >10% positive). Significant decreased time to progression (p=0.037) was seen in the subset of patients with p53 alteration (n=54) in comparison to the group with normatl p53 (n=20)", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:44 UTC", "nct_ids": null, "normalized_drug": [ "Carboplatin, Cisplatin" ], "phenotypes": null, "pub_med_references": [ 11595686 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "ALTERATION", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Breast Cancer", "doid": "1612", "drug_interaction_type": null, "drugs": [ "Tamoxifen" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2783", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In a study 202 breast cancer patients undergoing first line tamoxifen treatment, 65 patients had mutations in TP53. Among the p53 wild type population a 66% response rate was reported, where response was considered as complete response, partial response or stable disease. In a patient subgroup with mutations in p53 amino acids that directly interact with DNA, 2 of 11 (18%) of patients responded to tamoxifen.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": [ "Tamoxifen" ], "phenotypes": null, "pub_med_references": [ 10786679 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "DNA Binding Domain Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Breast Cancer", "doid": "1612", "drug_interaction_type": null, "drugs": [ "Tamoxifen" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2784", "evidence_direction": "Supports", "evidence_level": "C", "evidence_statement": "In a study 202 breast cancer patients undergoing tamoxifen treatment, a higher frequency of wildtype TP53 patients responded to treatment compared to those with mutations in TP53 (66% wild-type vs. 31%, odds ratio (OR):0.22, 95CI:0.12-0.42, P<0.0001, univariate analysis; OR:0.29, 95% CI:0.12-0.42, P=0.0014, multivariate analysis). The median survival after start of therapy was shorter in patients with mutations in TP53 than for patients with wild-type TP53 (20mo vs. 29mo, HR:1.99,95% CI:1.43-2.75, P<0.001). Breast cancer patients with TP53 mutations also had a decrease in progression-free survival (HR:2.61, 95% CI:1.90-3.6, P<0.001).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": [ "Tamoxifen" ], "phenotypes": null, "pub_med_references": [ 10786679 ], "rating": "1", "representative_transcript": null, "transcripts": null, "variant": "Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Stomach Cancer", "doid": "10534", "drug_interaction_type": null, "drugs": [ "Etoposide", "Mitomycin", "Cisplatin" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2799", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In a Phase II trial of 25 patients with metastaic gastric cancer, patients received preoperative high dose chemotherapy (HDCT) consisting of etoposide, cisplatin and mitomycin. Patients with greater than 50% regression in response to HDCT received surgery. TP53 overexpression was assayed by immunohistochemistry. 14 patients showed p53 overexpression, and 12 of these qualified for resection. Overall survival in patients with p53 overexpression was 17.3 months in contrast to patients with negative p53 immunohistochemistry, where it was 7.2 months (p=0.0003).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:44 UTC", "nct_ids": null, "normalized_drug": [ "Cisplatin", "Etoposide", "Mitomycin" ], "phenotypes": null, "pub_med_references": [ 14514923 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "Overexpression", "variant_civic_url": null, "variant_origin": null, "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Stomach Carcinoma", "doid": "5517", "drug_interaction_type": null, "drugs": [ "Doxorubicin", "Cisplatin", "Etoposide" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2820", "evidence_direction": "Supports", "evidence_level": "C", "evidence_statement": "In a study of 25 patients with advanced gastric cancer, mutations in TP53 were identified in 32% of primary tumors. TP53 mutations were associated with an improved response to preoperative treatment of a modified EAP protocol (combination of doxorubicin, etoposide and cisplatin). Patients with mutations in TP53 had an increased median survival compared to patients with wildtype TP53 (18.5mo vs. 10.2mo, P=0.044).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": [ "Cisplatin", "Doxorubicin", "Etoposide" ], "phenotypes": null, "pub_med_references": [ 14514923 ], "rating": "1", "representative_transcript": null, "transcripts": null, "variant": "Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Cancer", "doid": "162", "drug_interaction_type": null, "drugs": [ "Rebemadlin" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2963", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "MDM2 Inhibitor Nutlin-3a induced senescence in presence of functional TP53 in murine primary fibroblasts, oncogenically transformed fibroblasts, and fibrosarcoma cell lines. Cells lacking functional TP53 were completely insensitive to the drug.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:33 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 17671205 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "Wildtype", "variant_civic_url": null, "variant_origin": null, "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Cancer", "doid": "162", "drug_interaction_type": null, "drugs": [ "MDM2 Inhibitor AMGMDS3" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2964", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "MDM2 Inhibitor screen in a panel of 260 cancer cell lines with well characterized TP53 status shows that only cancer cell lines with unaltered TP53 may be sensitive to MDM2 Inhibitor.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:33 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 25730903 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "Wildtype", "variant_civic_url": null, "variant_origin": null, "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Leukemia", "doid": "1240", "drug_interaction_type": null, "drugs": [ "RG7112" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2965", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "Phase I Trial of RG7112 in 116 heavily pretreated patients with AML, ALL, CML, CLL, sCLL demonstrated sustained clinical improvement and induction of TP53 target genes in subset of patients with wild type TP53. 96 patients were tested for TP53 mutation and 19 cases of mutation were detected. No sustained clinical improvement or induction of TP53 target genes was observed in patients with mutant TP53.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:33 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 26459177 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "Wildtype", "variant_civic_url": null, "variant_origin": null, "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Leukemia", "doid": "1240", "drug_interaction_type": null, "drugs": [ "RG7112" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2966", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "Phase I Trial of MDM2 inhibitor RG7112 in 116 patients with AML, ALL, CML, CLL, sCLL demonstrated sustained clinical improvement and induction of TP53 target genes in subset of patients with wild type TP53. No sustained clinical improvement or induction of TP53 target genes was observed in patients with mutant TP53.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 26459177 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "Deleterious Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Cancer", "doid": "162", "drug_interaction_type": null, "drugs": [ "MDM2 Inhibitor AMGMDS3" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2967", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "MDM2 Inhibitor screen in a panel of 260 cancer cell lines with well characterized TP53 status shows that only cancer cell lines with unaltered TP53 may be sensitive to MDM2 Inhibitor AMGMDS3, while those with p53 mutations demonstrated resistance.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 25730903 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "Deleterious Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Cancer", "doid": "162", "drug_interaction_type": null, "drugs": [ "Rebemadlin" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2968", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "MDM2 Inhibitor Nutlin-3a induced senescence in presence of functional TP53 in murine primary fibroblasts, oncogenically transformed fibroblasts, and fibrosarcoma cell lines. TP53 mutant cells lacking functional TP53 were completely insensitive to the drug.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 17671205 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "Deleterious Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Ovarian Cancer", "doid": "2394", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2993", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "Patients with conserved domain p53 mutation (n=61) were compared with those with wild type or non-conserved domain p53 mutation (n=117) in a cohort of 178 invasive ovarian carcinoma patients who had undergone surgery. Overall survival was decreased in the cohort with conserved domian mutation (p=0.005). Conserved domain mutation was an independent factor in univariate (but not multivariate) analysis of overall survival with relative risk 1.70 (1.17-2.47, p<0.007).", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:44 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11595686 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "CONSERVED DOMAIN MUT", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": null, "disease": "Lung Non-small Cell Carcinoma", "doid": "3908", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2999", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "A pooled analysis to investigate the prognostic and predictive roles of TP53/KRAS and TP53/EGFR comutations (cm) in randomized trials of adjuvant chemotherapy compared to observational therapy encompassing a total of 3,553 patients. TP53/KRAS cm showed no prognostic effects but a borderline predictive effect (p=0,04) for negative effect of chemotherapy as compared to tp53/KRAS wt/wt. TP53/EGFR cm in was neither prognostic ( P = .83), nor significantly predictive ( P = .86). Similar results were observed for both groups for disease-free survival.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 28453411 ], "rating": "5", "representative_transcript": null, "transcripts": null, "variant": "Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Ovarian Cancer", "doid": "2394", "drug_interaction_type": null, "drugs": [ "Cisplatin", "Carboplatin" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/3013", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In a study involving patients with invasive ovarian carcinoma who had undergone surgery, a subset of 73 patients were classified via response to platinum-based chemotherapy as sensitive or resistant/refractory and tested for p53 overexpression (>10% postive stained nuclei). 78% of p53 negative patients were classified as sensitive, in compariston to 39% of p53 positive patients (p=0.001).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:44 UTC", "nct_ids": null, "normalized_drug": [ "Carboplatin, Cisplatin" ], "phenotypes": null, "pub_med_references": [ 11595686 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "Overexpression", "variant_civic_url": null, "variant_origin": null, "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Ovarian Cancer", "doid": "2394", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/3014", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In a study of invasive ovarian carcinoma patients who had undergone surgery, the p53 alteration variant was defined as p53 mutation or p53 overexpression by immunostain (>10% positive). Patients with p53 alterations showed increase in poor tumor cell differentiation (p<0.001) and increase in tumor cellular S-phase fraction (p<0.001). Out of 178 patients, p53 alteration (n=132) was associated with decreased overall survival in comparison to normal p53 (n=46), p=0.007.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:44 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11595686 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "ALTERATION", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Cancer", "doid": "162", "drug_interaction_type": null, "drugs": [ "MDM2 Inhibitor AMGMDS3" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/4888", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 R249S loss of function mutation is present in 1 cell line and it is insensitive to MDM2 Inhibitor AMGMDS3.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:47 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 25730903 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "R249S", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Cancer", "doid": "162", "drug_interaction_type": null, "drugs": [ "MDM2 Inhibitor AMGMDS3" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/4889", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 R280K loss of function mutation is present in 1 cell line and it is insensitive to MDM2 Inhibitor AMGMDS3.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:47 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 25730903 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "R280K", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Neomorphic", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/7531", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "The R282W mutation was used to create isogenic AML cell lines using MOLM13 and K526 lines. R282W/- cells showed resistance to chemotherapeutic agents and failure to induce p21, indicating disruption of p53 function. ChIP assays demonstrated reduced p53 occupation across the genome for most p53 variants tested, while R282W cells indicated mutant p53 neomorphic binding at sites not occupied by wt. RNAseq studies determined that a novel gene expression program was not induced in R282W cells at baseline or with DNA damage induced p53 signal activation, and that the signature of gene expression was most similar to that of p53 loss, indicating that R282W mutation does not induce a neomophic p53 function.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:40 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 31395785 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "R282W", "variant_civic_url": null, "variant_origin": "Unknown", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Solid Tumor", "doid": null, "drug_interaction_type": null, "drugs": [ "Pazopanib", "Vorinostat" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/7540", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "Patients with a hotspot TP53 mutation had a higher rate of SD ≥6 months/PR, longer median PFS, and median OS compared to patients without a hotspot TP53 mutation. Mutations observed in this study include loss of function (A159fs, R213*, and DNA-binding domain truncation) or gain of function (R175H, H179R, H193R, V216M, G245S, and R273C). These mutations were seen in 11 of 36 patients in enrolled in the clinical trial.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-11-23 19:14:39 UTC", "nct_ids": [ "NCT01339871" ], "normalized_drug": [ "Pazopanib", "Vorinostat" ], "phenotypes": null, "pub_med_references": [ 25669829 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "Mutation", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Medulloblastoma SHH Activated", "doid": "0080703", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/8347", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In the childhood (≥4.3 years) SHH-MB subgroup, TP53 mutations (n=13) are associated with shorter progression-free survival (PFS) compared to the no mutation group (n=35) (HR, 3.47; 95% CI, 1.29 to 9.3; p<0.014).", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:30 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 28545823 ], "rating": "5", "representative_transcript": null, "transcripts": null, "variant": "Mutation", "variant_civic_url": null, "variant_origin": null, "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Renal Wilms' Tumor", "doid": "5176", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/8945", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "44 archival FFPE samples from confirmed cases of Wilms tumor with mean age 3 years 2 months, and taken from the most histologically aggressive parts of each tumor, were stained with p53 monoclonal antibody and the corresponding patient clinical data was analyzed. 24 samples were p53 positive, and did not correlate with age or sex. All tumors with unfavorable histology were p53 positive, in contrast to 13 of 33 tumors with favorable histology, with weak-moderate p53 signal (p<0.001). 2 year overall survival rate was 89.2% in p53 negative, and 55.7% for p53 positive cases (P = .01), and mean survival was 46 months in p53 negative and 26 months in p53 positive cases (P = .02). Compared with p53 negative, tumors with week to moderate p53 signal had HR 3.75 (P = .05), and high signal had HR 8.61 (P = .01). No significant correlation was seen between tumor clinicopathological stage and p53 expression.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:44 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 21525573 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "Overexpression", "variant_civic_url": null, "variant_origin": null, "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Gain of Function", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/9285", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "In a pre-clinical study, wild-type and P250L TP53 were transiently overexpressed in the human osteosarcoma SaOS-2 cell line, which lacks endogenous p53. Immunofluorescence revealed that the P250L mutant cell line had reduced nuclear and increased cytoplasmic staining as compared to the wildtype. The punctate staining suggested that the P250L mutant forms large aggregates within the perinucleus. Chemical disruption of the microtubule assembly resulted in a shift from punctate to diffuse cytoplasmic staining in the P250L cell line. The oligomerization state of the wild type and P250L p53 was analyzed using Blue-Native PAGE (BN-PAGE) and western blot analysis: It was found that the wild type p53 appeared as monomers, tetramers and octamers while the P250L p53 formed large masses. More importantly, it was found that the formation of these aggregates by the P250L mutant could lead to co-aggregation of the wild-type p53, causing dominant negative activity. Additionally, the P250L mutant was found to inactivate the p53 paralogs, p63 and p73, while upregulating HSP70 and HSP90.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:07 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 21445056 ], "rating": "5", "representative_transcript": null, "transcripts": null, "variant": "P250L", "variant_civic_url": null, "variant_origin": "Unknown", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Rhabdomyosarcoma", "doid": "3247", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/9594", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "This study evaluated 641 cases of rhabdomyosarcoma (RMS) that were enrolled in the Children’s Oncology Group (COG) trials from 1998 to 2017 and the UK malignant mesenchymal tumor and RMS2005 trails from 1995 to 2016. Molecular testing included 39 genes which had been implicated in the past with regards to RMS. The analysis was performed with a custom-capture sequencing assay. Altered TP53 was noted in 69 out of 515 FOXO1 fusion-negative RMS cases (13%), with the most frequent mutations at codons G245S (6 cases), R248Q or W (6 cases), R175H (4 cases), and P72A (4 cases). These cases displayed a worse event free survival. In FOXO1 fusion-positive RMS subtype, there was a small number of cases with altered TP53 (3 and 2 cases in the COG and UK patient cohorts, respectively), but they were universally fatal. Due to lack of a matched germline sample, it could not be determined whether the TP53 abnormalities were of somatic or germline origin. Nevertheless, both cohorts show that mutations in TP53 are associated with a poor prognosis in both fusion-negative and fusion-positive RMS, with a particularly bleak outcome in fusion-positive RMS.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:44 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": [ "Pediatric onset", "Young adult onset" ], "pub_med_references": [ 34166060 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "ALTERATION", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Loss of Function", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/9805", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "Cancer-associated TP53 mutations were assessed for effects on the stability and oligomeric structure of p53. TP53 R324P protein eluted as a single peak contemporaneously with the known monomer mutant L330A, and separate from tetrameric TP53, during gel-filtration chromatography. The introduction of Proline at the solvent-exposed residue R342 inhibited tetramer formation resulting in p53 remaining in an unfolded monomeric state. Since formation of a tetramer is important for p53 function, destabilization of the tetrameric structure is likely to result in loss of p53 tumor suppressor activity.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:10 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 20978130 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "R342P", "variant_civic_url": null, "variant_origin": "Unknown", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Loss of Function", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/9808", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "Cancer-associated TP53 mutations were assessed for effects on the stability and oligomeric structure of p53. TP53 R337P protein eluted as a single peak contemporaneously with the known monomer mutant L330A, and separate from tetrameric TP53, during gel-filtration chromatography. The introduction of Proline at residue R337 in the hydrophobic core inhibited tetramer formation resulting in p53 remaining in an unfolded monomeric state. Since formation of a tetramer is important for p53 function, destabilization of the tetrameric structure is likely to result in loss of p53 tumor suppressor activity.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:10 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 20978130 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "R337P", "variant_civic_url": null, "variant_origin": "Unknown", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10215", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant P98S was classified as recessive for RGC and was not classified as a hotspot for mutation by the authors.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:11 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "P98S", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10216", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant P98L was classified as recessive for RGC and was not classified as a hotspot for mutation by the authors.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:11 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "P98L", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10217", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant Y126D was classified as recessive for RGC and was not classified as a hotspot for mutation by the authors.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:11 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "Y126D", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10218", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant Y126S was classified as recessive for RGC and was not classified as a hotspot for mutation by the authors.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:11 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "Y126S", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10219", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant K139E was classified as recessive for RGC and was not classified as a hotspot for mutation by the authors.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:11 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "K139E", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10224", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant I162F was classified as recessive for RGC and a hotspot for mutation (P < 0.014) by the authors.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:11 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "I162F", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10225", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant Y163H was classified as recessive for RGC and a hotspot for mutation (P < 0.001) by the authors.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:11 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "Y163H", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10226", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant Y236S was classified as recessive for RGC and a hotspot for mutation (P < 0.01) by the authors.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "Y236S", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10227", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant L252F was classified as recessive for RGC and was not classified as a hotspot for mutation by the authors.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "L252F", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10228", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant E258K was classified as recessive for RGC and a hotspot for mutation (P < 0.01) by the authors.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "E258K", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10229", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant G262D was classified as recessive for RGC and was not classified as a hotspot for mutation by the authors.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "G262D", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10230", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant G266R was classified as recessive for RGC and a hotspot for mutation (P < 0.001) by the authors.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:42 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "G266R", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10231", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant G266E was classified as recessive for RGC and a hotspot for mutation (P < 0.001) by the authors.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "G266E", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10233", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant P278S was classified as recessive for RGC and a hotspot for mutation (P < 0.001) by the authors.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:42 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "P278S", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10234", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "CAUTION: This Evidence Item has not been accepted as accurate or complete! A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant L308M was classified as recessive for RGC and was not classified as a hotspot for mutation by the authors.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "L308M", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10235", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "CAUTION: This Evidence Item has not been accepted as accurate or complete! A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant L323P was classified as recessive for RGC and was not classified as a hotspot for mutation by the authors.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "L323P", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10236", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant Q144P was classified as recessive for p21, bax, and PIG3. In addition, Q144P was not classified as a hotspot for mutation by the authors.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "Q144P", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10238", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant P219H was classified as recessive for p21, bax, and PIG3. In addition, P219H was not classified as a hotspot for mutation by the authors.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "P219H", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10239", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant Y220H was classified as recessive for RGC, p21, bax, and PIG3. In addition, Y220H was classified as a hotspot for mutation (P < 0.001) by the authors.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "Y220H", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10240", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant E224K was classified as recessive for RGC, p21, bax, and PIG3. In addition, E224K was not classified as a hotspot for mutation by the authors.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "E224K", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10241", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant Y234H was classified as recessive for RGC, p21, bax, and PIG3. In addition, Y234H was classified as a hotspot for mutation (P < 0.001) by the authors.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "Y234H", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10242", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant T230S was classified as recessive for RGC, p21, bax, and PIG3. In addition, T230S was not classified as a hotspot for mutation by the authors.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "T230S", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10243", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant H168Y was classified as dominant negative for p21, bax, and PIG3. In addition, H168Y was classified as a hotspot for mutation (P < 0.014) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "H168Y", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10244", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant P177S was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, P177S was classified as a hotspot for mutation (P < 0.01) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "P177S", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10245", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant P177F was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, P177F was classified as a hotspot for mutation (P < 0.01) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "P177F", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10246", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant P177H was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, P177H was classified as a hotspot for mutation (P < 0.01) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "P177H", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10247", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant H179Y was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, H179Y was classified as a hotspot for mutation (P < 0.001) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:42 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "H179Y", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10248", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant N239S was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, N239S was classified as a hotspot for mutation (P < 0.01) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "N239S", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10250", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant S241F was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, S241F was classified as a hotspot for mutation (P < 0.001) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:02 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "S241F", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10252", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant G244S was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, G244S was classified as a hotspot for mutation (P < 0.001) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:42 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "G244S", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10254", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant G245D was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, G245D was classified as a hotspot for mutation (P < 0.001) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:42 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "G245D", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10255", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant M246L was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, M246L was classified as a hotspot for mutation (P < 0.001) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "M246L", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10257", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant V274F was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, V274F was classified as a hotspot for mutation (P < 0.014) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "V274F", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10258", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant G279E was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, G279E was not classified as a hotspot for mutation by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "G279E", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10259", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant D281N was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, D281N was classified as a hotspot for mutation (P < 0.001) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "D281N", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10260", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant D281E was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, D281E was classified as a hotspot for mutation (P < 0.001) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:42 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "D281E", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10265", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant R156P was classified as recessive for RGC, p21, and PIG3, but it was classified as dominant negative for bax. In addition, R156P was classified as a hotspot for mutation (P < 0.01) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "2", "representative_transcript": null, "transcripts": null, "variant": "R156P", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10268", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant R181H was classified as recessive for RGC, p21, and PIG3, but it was classified as dominant negative for bax. In addition, R181H was classified as a hotspot for mutation (P < 0.01) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "2", "representative_transcript": null, "transcripts": null, "variant": "R181H", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10269", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant D259V was classified as recessive for RGC, p21, and PIG3, but it was classified as dominant negative for bax. In addition, D259V was classified as a hotspot for mutation (P < 0.01) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:08 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "2", "representative_transcript": null, "transcripts": null, "variant": "D259V", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10270", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant E286K was classified as recessive for RGC, p21, and PIG3, but it was classified as dominant negative for bax. In addition, E286K was classified as a hotspot for mutation (P < 0.01) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:39 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "2", "representative_transcript": null, "transcripts": null, "variant": "E286K", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10271", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant R283H was classified as recessive for p21 and PIG3, but it was classified as dominant negative for bax. In addition, R283H was classified as a hotspot for mutation (P < 0.01) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "2", "representative_transcript": null, "transcripts": null, "variant": "R283H", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10272", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant Y163N was classified as recessive for p21, but it was classified as dominant negative for bax and PIG3. In addition, Y163N was classified as a hotspot for mutation (P < 0.001) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "2", "representative_transcript": null, "transcripts": null, "variant": "Y163N", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10273", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant L257P was classified as recessive for p21, but it was classified as dominant negative for RGC, bax and PIG3. In addition, L257P was classified as a hotspot for mutation (P < 0.014) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 11896595 ], "rating": "2", "representative_transcript": null, "transcripts": null, "variant": "L257P", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10528", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant R156H originally identified in an oral lesion. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing p53 variant and WT p53 produced red/pink colonies, demonstrating that R156H displays transdominance. Authors reported that all of the DN mutants affected the amino acids essential to the upkeep of DNA binding surfaces according to crystallographic structure.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:14 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 10519380 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "R156H", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10529", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant H178P originally identified in glioblastoma. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing p53 variant and WT p53 produced red/pink colonies, demonstrating that H178P displays transdominance. Authors reported that all of the DN mutants affected the amino acids essential to the upkeep of DNA binding surfaces according to crystallographic structure.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:14 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 10519380 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "H178P", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10530", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant H179R originally identified in an oral lesion. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing p53 variant and WT p53 produced red/pink colonies, demonstrating that H179R displays transdominance. Authors reported that all of the DN mutants affected the amino acids essential to the upkeep of DNA binding surfaces according to crystallographic structure.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:42 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 10519380 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "H179R", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10531", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant R181P originally identified in breast cancer. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing p53 variant and WT p53 produced red/pink colonies, demonstrating that R181P displays transdominance. Authors reported that all of the DN mutants affected the amino acids essential to the upkeep of DNA binding surfaces according to crystallographic structure.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:08 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 10519380 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "R181P", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10540", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant R249S. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing p53 variant and WT p53 produced red/pink colonies, demonstrating that R249S displays transdominance. Authors reported that all of the DN mutants affected the amino acids essential to the upkeep of DNA binding surfaces according to crystallographic structure.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:47 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 10519380 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "R249S", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10554", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant L111R originally identified in anaplastic astrocytoma. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing L111R and WT p53 produced white colonies, indicating that L111R is not DN.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:14 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 10519380 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "L111R", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10555", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant H115Y originally identified in anaplastic astrocytoma from a glioma cell line. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing H115Y and WT p53 produced white colonies, indicating that H115Y is not DN.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:14 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 10519380 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "H115Y", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10556", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant C124R originally identified in anaplastic astrocytoma. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing C124R and WT p53 produced white colonies, indicating that C124R is not DN.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:14 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 10519380 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "C124R", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10558", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant L139N originally identified in breast cancer. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing L139N and WT p53 produced white colonies, indicating that L139N is not DN.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:14 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 10519380 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "L139N", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10574", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant G266V originally identified in breast cancer. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing G266V and WT p53 produced white colonies, indicating that G266V is not DN.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:14 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 10519380 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "G266V", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10575", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant G266E originally identified in glioblastoma from a glioma cell line. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing G266E and WT p53 produced white colonies, indicating that G266E is not DN.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:47:12 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 10519380 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "G266E", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." }, { "asco_entry": null, "clinical_significance": "Dominant Negative", "disease": null, "doid": null, "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/10576", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant F270S originally identified in breast cancer. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing F270S and WT p53 produced white colonies, indicating that F270S is not DN.", "evidence_status": "accepted", "evidence_type": "Functional", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:42 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 10519380 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "F270S", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "gene_description": "TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate." } ] }, "dbnsfp_genes": { "version": "4.5", "items": [ { "kegg": { "id": [ "hsa04010", "hsa04110", "hsa04115", "hsa04210", "hsa04310", "hsa05030", "hsa05040", "hsa05210", "hsa05212", "hsa05213", "hsa05214", "hsa05215", "hsa05216", "hsa05217", "hsa05218", "hsa05219", "hsa05220", "hsa05222", "hsa05223" ], "full": [ "MAPK signaling pathway", "Cell cycle", "p53 signaling pathway", "Apoptosis", "Wnt signaling pathway", "Amyotrophic lateral sclerosis (ALS)", "Huntington's disease", "Colorectal cancer", "Pancreatic cancer", "Endometrial cancer", "Glioma", "Prostate cancer", "Thyroid cancer", "Basal cell carcinoma", "Melanoma", "Bladder cancer", "Chronic myeloid leukemia", "Small cell lung cancer", "Non-small cell lung cancer" ] }, "expressions_rpkm": null, "gene_symbol": "TP53", "p_hi": 1.0, "gdi": 15.33, "gdi_phred": 0.5512, "loftool_score": 0.0009650000000000004, "hipred": 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Acetylation", "Autodegradation of the E3 ubiquitin ligase COP1", "Stabilization of p53", "Transcriptional activation of cell cycle inhibitor p21", "Transcriptional activation of p53 responsive genes", "p53-Dependent G1 DNA Damage Response", "p53-Dependent G1/S DNA damage checkpoint", "G1/S DNA Damage Checkpoints", "G2/M DNA damage checkpoint", "Activation of NOXA and translocation to mitochondria", "Activation of PUMA and translocation to mitochondria", "Activation of BH3-only proteins", "G2/M Checkpoints", "Chaperonin-mediated protein folding", "Intrinsic Pathway for Apoptosis", "Cell Cycle Checkpoints", "Oncostatin_M", "Association of TriC/CCT with target proteins during biosynthesis", "Apoptosis", "Programmed Cell Death", "Hypoxic and oxygen homeostasis regulation of HIF-1-alpha", "Pre-NOTCH Transcription and Translation", "Pre-NOTCH Expression and Processing", "Signaling by NOTCH", "TP53 Regulates Metabolic Genes", "Aurora A signaling", "SUMOylation", "TP53 Regulates Transcription of Genes Involved in Cytochrome C Release", "cell cycle: g2/m checkpoint", "regulation of transcriptional activity by pml", "TP53 Regulates Transcription of Caspase Activators and Caspases", "Cellular responses to external stimuli", "TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain", "TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest", "p53 signaling pathway", "TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest", "atm signaling pathway", "TGF_beta_Receptor", "TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain", "TP53 Regulates Transcription of Cell Cycle Genes", "EGFR1", "TP53 Regulates Transcription of DNA Repair Genes", "Regulation of TP53 Expression", "Glucocorticoid receptor regulatory network", "Regulation of PTEN gene transcription", "The role of GTSE1 in G2/M progression after G2 checkpoint", "Hemostasis", "Ub-specific processing proteases", "rb tumor suppressor/checkpoint signaling in response to dna damage", "Regulation of TP53 Degradation", "Regulation of TP53 Expression and Degradation", "G2/M Transition", "Mitotic G2-G2/M phases", "PTEN Regulation", "PIP3 activates AKT signaling", "Ovarian tumor domain proteases", "Protein folding", "Deubiquitination", "Regulation of TP53 Activity through Phosphorylation", "Regulation of TP53 Activity through Association with Co-factors", "Regulation of TP53 Activity through Methylation", "Regulation of TP53 Activity through Acetylation", "Regulation of TP53 Activity", "Transcriptional Regulation by TP53", "Direct p53 effectors", "Cell Cycle", "Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks", "DNA Double Strand Break Response", "Cell Cycle, Mitotic", "Intracellular signaling by second messengers", "Signaling mediated by p38-alpha and p38-beta", "PLK3 signaling events", "Validated targets of C-MYC transcriptional activation", "AP-1 transcription factor network", "BARD1 signaling events", "p75(NTR)-mediated signaling", "Signaling events mediated by HDAC Class III", "p53 pathway", "LKB1 signaling events", "TP53 Regulates Transcription of Death Receptors and Ligands" ], "expression_gnf_atlas": [ "white blood cells", "superior cervical ganglion", "atrioventricular node", "placenta", "skeletal muscle" ], "expression_egenetics": [ "thymus", "epididymis", "tongue", "skin", "stomach", "testis", "lymphoreticular", "amniotic fluid", "larynx", "kidney", "uterus", "pancreas", "bile duct", "head and neck", "hypopharynx", "mammary gland", "skeletal muscle", "mesenchyma", "islets of Langerhans", "cervix", "vein", "spleen", "liver", "cartilage", "endometrium", "bone", "germinal center", "brain", "blood", "bone marrow", "lung", "ovary", "thyroid", "lymph node", "bladder", "frontal lobe", "colon", "placenta", "prostate", "breast" ], "pathway_uniprot": null, "function_description": "Acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on the physiological circumstances and cell type. Involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process. One of the activated genes is an inhibitor of cyclin-dependent kinases. Apoptosis induction seems to be mediated either by stimulation of BAX and FAS antigen expression, or by repression of Bcl-2 expression. In cooperation with mitochondrial PPIF is involved in activating oxidative stress-induced necrosis; the function is largely independent of transcription. Induces the transcription of long intergenic non-coding RNA p21 (lincRNA-p21) and lincRNA- Mkln1. LincRNA-p21 participates in TP53-dependent transcriptional repression leading to apoptosis and seems to have an effect on cell-cycle regulation. Implicated in Notch signaling cross-over. Prevents CDK7 kinase activity when associated to CAK complex in response to DNA damage, thus stopping cell cycle progression. Isoform 2 enhances the transactivation activity of isoform 1 from some but not all TP53-inducible promoters. Isoform 4 suppresses transactivation activity and impairs growth suppression mediated by isoform 1. Isoform 7 inhibits isoform 1-mediated apoptosis. Regulates the circadian clock by repressing CLOCK-ARNTL/BMAL1- mediated transcriptional activation of PER2 (PubMed:24051492). ", "disease_description": [ "TP53 is found in increased amounts in a wide variety of transformed cells. TP53 is frequently mutated or inactivated in about 60% of cancers. TP53 defects are found in Barrett metaplasia a condition in which the normally stratified squamous epithelium of the lower esophagus is replaced by a metaplastic columnar epithelium. The condition develops as a complication in approximately 10% of patients with chronic gastroesophageal reflux disease and predisposes to the development of esophageal adenocarcinoma", "Esophageal cancer (ESCR) [MIM:133239]: A malignancy of the esophagus. The most common types are esophageal squamous cell carcinoma and adenocarcinoma. Cancer of the esophagus remains a devastating disease because it is usually not detected until it has progressed to an advanced incurable stage. The disease is caused by mutations affecting the gene represented in this entry", "Li-Fraumeni syndrome (LFS) [MIM:151623]: An autosomal dominant familial cancer syndrome that in its classic form is defined by the existence of a proband affected by a sarcoma before 45 years with a first degree relative affected by any tumor before 45 years and another first degree relative with any tumor before 45 years or a sarcoma at any age. Other clinical definitions for LFS have been proposed and called Li-Fraumeni like syndrome (LFL). In these families affected relatives develop a diverse set of malignancies at unusually early ages. Four types of cancers account for 80% of tumors occurring in TP53 germline mutation carriers: breast cancers, soft tissue and bone sarcomas, brain tumors (astrocytomas) and adrenocortical carcinomas. Less frequent tumors include choroid plexus carcinoma or papilloma before the age of 15, rhabdomyosarcoma before the age of 5, leukemia, Wilms tumor, malignant phyllodes tumor, colorectal and gastric cancers. ", "Squamous cell carcinoma of the head and neck (HNSCC) [MIM:275355]: A non-melanoma skin cancer affecting the head and neck. The hallmark of cutaneous SCC is malignant transformation of normal epidermal keratinocytes. The gene represented in this entry is involved in disease pathogenesis", "Lung cancer (LNCR) [MIM:211980]: A common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis. The disease is caused by mutations affecting the gene represented in this entry", "Papilloma of choroid plexus (CPP) [MIM:260500]: A benign tumor of neuroectodermal origin that generally occurs in childhood, but has also been reported in adults. Although generally found within the ventricular system, choroid plexus papillomas can arise ectopically in the brain parenchyma or disseminate throughout the neuraxis. Patients present with signs and symptoms of increased intracranial pressure including headache, hydrocephalus, papilledema, nausea, vomiting, cranial nerve deficits, gait impairment, and seizures. ", "Adrenocortical carcinoma (ADCC) [MIM:202300]: A malignant neoplasm of the adrenal cortex and a rare childhood tumor. It occurs with increased frequency in patients with Beckwith- Wiedemann syndrome and Li-Fraumeni syndrome. ", "Basal cell carcinoma 7 (BCC7) [MIM:614740]: A common malignant skin neoplasm that typically appears on hair-bearing skin, most commonly on sun-exposed areas. It is slow growing and rarely metastasizes, but has potentialities for local invasion and destruction. It usually develops as a flat, firm, pale area that is small, raised, pink or red, translucent, shiny, and waxy, and the area may bleed following minor injury. Tumor size can vary from a few millimeters to several centimeters in diameter. " ], "gene_damage_prediction": { "primary_immunodeficiency": { "autosomalrecessive": "Medium", "autosomaldominant": "Medium", "all": "Medium" }, "mendelian": { "autosomalrecessive": "Medium", "autosomaldominant": "Medium", "all": "Medium" }, "cancer": { "recessive": "Medium", "dominant": "Medium", "all": "Medium" }, "all": "Medium" }, "mgi_mouse_gene": "Trp53", "mgi_mouse_phenotype": [ "behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)", "liver/biliary system phenotype", "respiratory system phenotype", "embryo phenotype", "neoplasm", "pigmentation phenotype", "normal phenotype", "mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span)", "reproductive system phenotype", "hematopoietic system phenotype", "cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan)", "vision/eye phenotype", "limbs/digits/tail phenotype", "hearing/vestibular/ear phenotype", "nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan)", "digestive/alimentary phenotype", "renal/urinary system phenotype", "skeleton phenotype", "cellular phenotype", "immune system phenotype", "homeostasis/metabolism phenotype", "adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan)", "endocrine/exocrine gland phenotype", "integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan)", "growth/size/body region phenotype", "craniofacial phenotype", "muscle phenotype" ], "zfin_zebrafish_gene": "tp53", "zfin_zebrafish_structure": "nucleate erythrocyte", "zfin_zebrafish_phenotype_quality": "immature", "zfin_zebrafish_phenotype_tag": "abnormal" } ] }, "exac_genes": { "version": "18-Sep-2018", "items": [ { "prec": 0.08775030000000002, "pnull": 0.0000267186, "pli": 0.912223, "syn_z": -0.042240200000000006, "mis_z": 1.37892, "cnv_score": -0.19665500000000002, "segdups": 0, "flag": false } ] }, "publications": { "publications": [], "genes": [ { "publications": [ { "referenced_by": [ "VarSome AI" ], "pub_med_id": 38605929 }, { "referenced_by": [ "VarSome AI" ], "pub_med_id": 38588886 }, { "referenced_by": [ "VarSome AI" ], "pub_med_id": 38565739 }, { "referenced_by": [ 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This protein acts as a tumor suppressor, which means that it regulates cell division by keeping cells from growing and dividing (proliferating) too fast or in an uncontrolled way.</p><p>The p53 protein is located in the nucleus of cells throughout the body, where it attaches (binds) directly to DNA. When the DNA in a cell becomes damaged by agents such as toxic chemicals, radiation, or ultraviolet (UV) rays from sunlight, this protein plays a critical role in determining whether the DNA will be repaired or the damaged cell will self-destruct (undergo apoptosis). If the DNA can be repaired, p53 activates other genes to fix the damage. If the DNA cannot be repaired, this protein prevents the cell from dividing and signals it to undergo apoptosis. By stopping cells with mutated or damaged DNA from dividing, p53 helps prevent the development of tumors.</p><p>Because p53 is essential for regulating DNA repair and cell division, it has been nicknamed the \"guardian of the genome.\"</p>", "date_published_by_ghr": "2023-05-04", "conditions_list": [ { "name": "Bladder Cancer", "html_text": "<p>Bladder cancer is a disease in which certain cells in the bladder become abnormal and multiply uncontrollably to form a tumor. The bladder is a muscular organ in the lower abdomen that stores urine until it can be removed (excreted) from the body.</p><p>Bladder cancer may cause blood in the urine, pain during urination, frequent urination, the feeling of needing to urinate without being able to, or lower back pain. Many of these signs and symptoms are nonspecific, which means they may occur in multiple disorders. People who have one or more of these nonspecific health problems often do not have bladder cancer, but have another condition such as an infection.</p><p>Bladder cancer develops when tumors form in the tissue that lines the bladder. There are several types of bladder cancer, categorized by the type of cell in the tissue that becomes cancerous. The most common type is transitional cell carcinoma (also known as urothelial carcinoma); others include squamous cell carcinoma and adenocarcinoma. If the tumor spreads u00a0(metastasizes) beyond the lining of the bladder into nearby tissues or organs, it is known as invasive bladder cancer.u00a0</p>", "ghr_link": "https://medlineplus.gov/genetics/condition/bladder-cancer", "db_key_list": [ { "gtr": "C0699885" }, { "icd_10_cm": "C67" }, { "icd_10_cm": "C67.0" }, { "icd_10_cm": "C67.1" }, { "icd_10_cm": "C67.2" }, { "icd_10_cm": "C67.3" }, { "icd_10_cm": "C67.4" }, { "icd_10_cm": "C67.5" }, { "icd_10_cm": "C67.6" }, { "icd_10_cm": "C67.7" }, { "icd_10_cm": "C67.8" }, { "icd_10_cm": "C67.9" }, { "icd_10_cm": "D09.0" }, { "mesh": "D001749" }, { "omim": "109800" }, { "snomed_ct": "126885006" }, { "snomed_ct": "255108000" }, { "snomed_ct": "399326009" } ] }, { "name": "Breast Cancer", "html_text": "<p>Breast cancer is a disease in which certain cells in the breast become abnormal and multiply uncontrollably to form a tumor. Although breast cancer is much more common in women, this form of cancer can also develop in men. In both women and men, the most common form of breast cancer begins in cells lining the milk ducts (ductal cancer). In women, cancer can also develop in the glands that produce milk (lobular cancer). Most men have little or no lobular tissue, so lobular cancer in men is very rare. </p><p>In its early stages, breast cancer usually does not cause pain and may exhibit no noticeable symptoms. As the cancer progresses, signs and symptoms can include a lump or thickening in or near the breast; a change in the size or shape of the breast; nipple discharge, tenderness, or retraction (turning inward); and skin irritation, dimpling, redness, or scaliness. However, these changes can occur as part of many different conditions. Having one or more of these symptoms does not mean that a person definitely has breast cancer.</p><p>In some cases, cancerous cells can invade surrounding breast tissue. In these cases, the condition is known as invasive breast cancer. Sometimes, tumors spread to other parts of the body. If breast cancer spreads, cancerous cells most often appear in the bones, liver, lungs, or brain. Tumors that begin at one site and then spread to other areas of the body are called metastatic cancers.</p><p>A small percentage of all breast cancers cluster in families. These cancers are described as hereditary and are associated with inherited gene mutations. Hereditary breast cancers tend to develop earlier in life than noninherited (sporadic) cases, and new (primary) tumors are more likely to develop in both breasts.</p>", "ghr_link": "https://medlineplus.gov/genetics/condition/breast-cancer", "db_key_list": [ { "gtr": "C0006142" }, { "gtr": "C1861906" }, { "gtr": "C3469522" }, { "icd_10_cm": "C50.01" }, { "icd_10_cm": "C50.011" }, { "icd_10_cm": "C50.012" }, { "icd_10_cm": "C50.019" }, { "icd_10_cm": "C50.02" }, { "icd_10_cm": "C50.021" }, { "icd_10_cm": "C50.022" }, { "icd_10_cm": "C50.029" }, { "icd_10_cm": "C50.11" }, { "icd_10_cm": "C50.111" }, { "icd_10_cm": "C50.112" }, { "icd_10_cm": "C50.119" }, { "icd_10_cm": "C50.21" }, { "icd_10_cm": "C50.211" }, { "icd_10_cm": "C50.212" }, { "icd_10_cm": "C50.219" }, { "icd_10_cm": "C50.22" }, { "icd_10_cm": "C50.221" }, { "icd_10_cm": "C50.222" }, { "icd_10_cm": "C50.229" }, { "icd_10_cm": "C50.31" }, { "icd_10_cm": "C50.311" }, { "icd_10_cm": "C50.312" }, { "icd_10_cm": "C50.319" }, { "icd_10_cm": "C50.32" }, { "icd_10_cm": "C50.321" }, { "icd_10_cm": "C50.322" }, { "icd_10_cm": "C50.329" }, { "icd_10_cm": "C50.41" }, { "icd_10_cm": "C50.411" }, { "icd_10_cm": "C50.412" }, { "icd_10_cm": "C50.419" }, { "icd_10_cm": "C50.42" }, { "icd_10_cm": "C50.421" }, { "icd_10_cm": "C50.422" }, { "icd_10_cm": "C50.429" }, { "icd_10_cm": "C50.51" }, { "icd_10_cm": "C50.511" }, { "icd_10_cm": "C50.512" }, { "icd_10_cm": "C50.519" }, { "icd_10_cm": "C50.52" }, { "icd_10_cm": "C50.521" }, { "icd_10_cm": "C50.522" }, { "icd_10_cm": "C50.529" }, { "icd_10_cm": "C50.61" }, { "icd_10_cm": "C50.611" }, { "icd_10_cm": "C50.612" }, { "icd_10_cm": "C50.619" }, { "icd_10_cm": "C50.62" }, { "icd_10_cm": "C50.621" }, { "icd_10_cm": "C50.622" }, { "icd_10_cm": "C50.629" }, { "icd_10_cm": "C50.81" }, { "icd_10_cm": "C50.811" }, { "icd_10_cm": "C50.812" }, { "icd_10_cm": "C50.819" }, { "icd_10_cm": "C50.82" }, { "icd_10_cm": "C50.821" }, { "icd_10_cm": "C50.822" }, { "icd_10_cm": "C50.829" }, { "icd_10_cm": "C50.91" }, { "icd_10_cm": "C50.911" }, { "icd_10_cm": "C50.912" }, { "icd_10_cm": "C50.919" }, { "icd_10_cm": "C50.92" }, { "icd_10_cm": "C50.921" }, { "icd_10_cm": "C50.922" }, { "icd_10_cm": "C50.929" }, { "icd_10_cm": "D05.0" }, { "icd_10_cm": "D05.00" }, { "icd_10_cm": "D05.01" }, { "icd_10_cm": "D05.02" }, { "icd_10_cm": "D05.1" }, { "icd_10_cm": "D05.10" }, { "icd_10_cm": "D05.11" }, { "icd_10_cm": "D05.12" }, { "icd_10_cm": "D05.9" }, { "icd_10_cm": "D05.90" }, { "icd_10_cm": "D05.91" }, { "icd_10_cm": "D05.92" }, { "icd_10_cm": "Z15.01" }, { "icd_10_cm": "Z80.3" }, { "mesh": "D001943" }, { "omim": "114480" }, { "omim": "604370" }, { "omim": "612555" }, { "snomed_ct": "126926005" }, { "snomed_ct": "254837009" }, { "snomed_ct": "254838004" }, { "snomed_ct": "254843006" }, { "snomed_ct": "865954003" } ] }, { "name": "Li-Fraumeni Syndrome", "html_text": "<p>Li-Fraumeni syndrome is a rare disorder that greatly increases the risk of developing several types of cancer, particularly in children and young adults.</p><p>The cancers most often associated with Li-Fraumeni syndrome include breast cancer, a form of bone cancer called osteosarcoma, and cancers of soft tissues (such as muscle) called soft tissue sarcomas. Other cancers commonly seen in this syndrome include brain tumors, cancers of blood-forming tissues (leukemias), and a cancer called adrenocortical carcinoma that affects the outer layer of the adrenal glands (small hormone-producing glands on top of each kidney). Several other types of cancer also occur more frequently in people with Li-Fraumeni syndrome.</p><p>A very similar condition called Li-Fraumeni-like syndrome shares many of the features of classic Li-Fraumeni syndrome. Both conditions significantly increase the chances of developing multiple cancers beginning in childhood; however, the pattern of specific cancers seen in affected family members is different.</p>", "ghr_link": "https://medlineplus.gov/genetics/condition/li-fraumeni-syndrome", "db_key_list": [ { "gtr": "C0085390" }, { "gtr": "C1835398" }, { "gtr": "C1836482" }, { "icd_10_cm": "Z15.01" }, { "mesh": "D016864" }, { "omim": "151623" }, { "omim": "609265" }, { "snomed_ct": "428850001" } ] }, { "name": "Head And Neck Squamous Cell Carcinoma", "html_text": "<p>Squamous cell carcinoma is a cancer that arises from particular cells called squamous cells. Squamous cells are found in the outer layer of skin and in the mucous membranes, which are the moist tissues that line body cavities such as the airways and intestines. Head and neck squamous cell carcinoma (HNSCC) develops in the mucous membranes of the mouth, nose, and throat.</p><p>HNSCC is classified by its location: it can occur in the mouth (oral cavity), the middle part of the throat near the mouth (oropharynx), the space behind the nose (nasal cavity and paranasal sinuses), the upper part of the throat near the nasal cavity (nasopharynx), the voicebox (larynx), or the lower part of the throat near the larynx (hypopharynx). Depending on the location, the cancer can cause abnormal patches or open sores (ulcers) in the mouth and throat, unusual bleeding or pain in the mouth, sinus congestion that does not clear, sore throat, earache, pain when swallowing or difficulty swallowing, a hoarse voice, difficulty breathing, or enlarged lymph nodes.</p><p>HNSCC can spread (metastasize) to other parts of the body, such as the lymph nodes or lungs. If it spreads, the cancer has a worse prognosis and can be fatal. About half of affected individuals survive more than five years after diagnosis.</p>", "ghr_link": "https://medlineplus.gov/genetics/condition/head-and-neck-squamous-cell-carcinoma", "db_key_list": [ { "gtr": "C1168401" }, { "mesh": "D002294" }, { "mesh": "D006258" }, { "omim": "275355" }, { "snomed_ct": "405822008" }, { "snomed_ct": "408649007" }, { "snomed_ct": "419842002" } ] }, { "name": "Ovarian Cancer", "html_text": "<p>Ovarian cancer is a disease that affects women. In this form of cancer, certain cells in the ovary become abnormal and multiply uncontrollably to form a tumor. The ovaries are the female reproductive organs in which egg cells are produced. In about 90 percent of cases, ovarian cancer occurs after age 40, and most cases occur after age 60.</p><p>The most common form of ovarian cancer begins in epithelial cells, which are the cells that line the surfaces and cavities of the body. These cancers can arise in the epithelial cells on the surface of the ovary. However, researchers suggest that many or even most ovarian cancers begin in epithelial cells on the fringes (fimbriae) at the end of one of the fallopian tubes, and the cancerous cells migrate to the ovary.</p><p>Cancer can also begin in epithelial cells that form the lining of the abdomen (the peritoneum). This form of cancer, called primary peritoneal cancer, resembles epithelial ovarian cancer in its origin, symptoms, progression, and treatment. Primary peritoneal cancer often spreads to the ovaries. It can also occur even if the ovaries have been removed. Because cancers that begin in the ovaries, fallopian tubes, and peritoneum are so similar and spread easily from one of these structures to the others, they are often difficult to distinguish. These cancers are so closely related that they are generally considered collectively by experts.</p><p>In about 10 percent of cases, ovarian cancer develops not in epithelial cells but in germ cells, which are precursors to egg cells, or in hormone-producing ovarian cells called granulosa cells.</p><p>In its early stages, ovarian cancer usually does not cause noticeable symptoms. As the cancer progresses, signs and symptoms can include pain or a feeling of heaviness in the pelvis or lower abdomen, bloating, feeling full quickly when eating, back pain, vaginal bleeding between menstrual periods or after menopause, or changes in urinary or bowel habits. However, these changes can occur as part of many different conditions. Having one or more of these symptoms does not mean that a woman has ovarian cancer.</p><p>In some cases, cancerous tumors can invade surrounding tissue and spread to other parts of the body. If ovarian cancer spreads, cancerous tumors most often appear in the abdominal cavity or on the surfaces of nearby organs such as the bladder or colon. Tumors that begin at one site and then spread to other areas of the body are called metastatic cancers.</p><p>Some ovarian cancers cluster in families. These cancers are described as hereditary and are associated with inherited gene mutations. Hereditary ovarian cancers tend to develop earlier in life than non-inherited (sporadic) cases.</p><p>Because it is often diagnosed at a late stage, ovarian cancer can be difficult to treat; it leads to the deaths of about 14,000 women annually in the United States, more than any other gynecological cancer. However, when it is diagnosed and treated early, the 5-year survival rate is high.</p>", "ghr_link": "https://medlineplus.gov/genetics/condition/ovarian-cancer", "db_key_list": [ { "gtr": "C1140680" }, { "icd_10_cm": "C56" }, { "icd_10_cm": "C56.1" }, { "icd_10_cm": "C56.2" }, { "icd_10_cm": "C56.9" }, { "mesh": "D010051" }, { "omim": "167000" }, { "omim": "604370" }, { "omim": "607893" }, { "omim": "612555" }, { "omim": "613399" }, { "omim": "614291" }, { "snomed_ct": "363443007" } ] }, { "name": "Lung Cancer", "html_text": "<p>Lung cancer is a disease in which certain cells in the lungs become abnormal and multiply uncontrollably to form a tumor. Lung cancer may not cause signs or symptoms in its early stages. Some people with lung cancer have chest pain, frequent coughing, blood in the mucus, breathing problems, trouble swallowing or speaking, loss of appetite and weight loss, fatigue, or swelling in the face or neck. Additional symptoms can develop if the cancer spreads (metastasizes) into other tissues. Lung cancer occurs most often in adults in their sixties or seventies. Most people who develop lung cancer have a history of long-term tobacco smoking; however, the condition can occur in people who have never smoked.</p><p>Lung cancer is generally divided into two types, small cell lung cancer and non-small cell lung cancer, based on the size of the affected cells when viewed under a microscope. Non-small cell lung cancer accounts for 85 percent of lung cancer, while small cell lung cancer accounts for the remaining 15 percent.</p><p>Small cell lung cancer grows quickly and in more than half of cases the cancer has spread beyond the lung by the time the condition is diagnosed. Small cell lung cancer often metastasizes, most commonly to the liver, brain, bones, and adrenal glands (small hormone-producing glands located on top of each kidney). After diagnosis, most people with small cell lung cancer survive for about 1 year; less than seven percent survive 5 years.</p><p>Non-small cell lung cancer is divided into three main subtypes: adenocarcinoma, squamous cell carcinoma, and large cell lung carcinoma. Adenocarcinoma arises from the cells that line the small air sacs (alveoli) located throughout the lungs. Squamous cell carcinoma arises from squamous cells that line the passages leading from the windpipe (trachea) to the lungs (bronchi). Large cell carcinoma arises from epithelial cells that line the lungs. Large cell carcinoma encompasses non-small cell lung cancers that do not appear to be adenocarcinomas or squamous cell carcinomas. The 5-year survival rate for people with non-small cell lung cancer is usually between 11 and 17 percent; it can be lower or higher depending on the subtype and stage of the cancer.</p>", "ghr_link": "https://medlineplus.gov/genetics/condition/lung-cancer", "db_key_list": [ { "gtr": "C0684249" }, { "icd_10_cm": "C34" }, { "icd_10_cm": "C34.0" }, { "icd_10_cm": "C34.00" }, { "icd_10_cm": "C34.01" }, { "icd_10_cm": "C34.02" }, { "icd_10_cm": "C34.1" }, { "icd_10_cm": "C34.10" }, { "icd_10_cm": "C34.11" }, { "icd_10_cm": "C34.12" }, { "icd_10_cm": "C34.2" }, { "icd_10_cm": "C34.3" }, { "icd_10_cm": "C34.30" }, { "icd_10_cm": "C34.31" }, { "icd_10_cm": "C34.32" }, { "icd_10_cm": "C34.9" }, { "icd_10_cm": "C34.90" }, { "icd_10_cm": "C34.91" }, { "icd_10_cm": "C34.92" }, { "mesh": "D002289" }, { "mesh": "D008175" }, { "mesh": "D055752" }, { "omim": "211980" }, { "snomed_ct": "363358000" }, { "snomed_ct": "830151004" } ] }, { "name": "Cholangiocarcinoma", "html_text": "<p>Cholangiocarcinoma is a group of cancers that begin in the bile ducts. Bile ducts are branched tubes that connect the liver and gallbladder to the small intestine. They carry bile, which is a fluid that helps the body digest fats that are in food. Bile is made in the liver and stored in the gallbladder before being released in the small intestine after a person eats.</p><p>Cholangiocarcinoma is classified by its location in relation to the liver. Intrahepatic cholangiocarcinoma begins in the small bile ducts within the liver. This is the least common form of the disease, accounting for less than 10 percent of all cases. Perihilar cholangiocarcinoma (also known as a Klatskin tumor) begins in an area called the hilum, where the right and left major bile ducts join and leave the liver. It is the most common form of the disease, accounting for more than half of all cases. The remaining cases are classified as distal cholangiocarcinomas, which begin in bile ducts outside the liver. The perihilar and distal forms of the disease, which both occur outside the liver, are sometimes grouped together and called extrahepatic cholangiocarcinoma.</p><p>The three types of cholangiocarcinoma do not usually cause any symptoms in their early stages, and this cancer is usually not diagnosed until it has already spread beyond the bile ducts to other tissues. Symptoms often result when bile ducts become blocked by the tumor. The most common symptom is jaundice, in which the skin and whites of the eyes turn yellow. Other symptoms can include extreme tiredness (fatigue), itching, dark-colored urine, loss of appetite, unintentional weight loss, abdominal pain, and light-colored and greasy stools. These symptoms are described as \"nonspecific\" because they can be features of many different diseases.</p><p>Most people who develop cholangiocarcinoma are older than 65. Because this cancer is often not discovered until it has already spread, it can be challenging to treat effectively. Affected individuals can survive for several months to several years after diagnosis, depending on the location of the cancer and how advanced it is.</p>", "ghr_link": "https://medlineplus.gov/genetics/condition/cholangiocarcinoma", "db_key_list": [ { "gtr": "C3810156" }, { "icd_10_cm": "C22.1" }, { "mesh": "D018281" }, { "omim": "615619" }, { "snomed_ct": "312104005" }, { "snomed_ct": "70179006" } ] }, { "name": "Wilms Tumor", "html_text": "<p>Wilms tumor is a form of kidney cancer that primarily develops in children. Nearly all cases of Wilms tumor are diagnosed before the age of 10, with two-thirds being found before age 5.</p><p>Wilms tumor is often first noticed because of abdominal swelling or a mass in the kidney that can be felt upon physical examination. Some affected children have abdominal pain, fever, a low number of red blood cells (anemia), blood in the urine (hematuria), or high blood pressure (hypertension). Additional signs of Wilms tumor can include loss of appetite, weight loss, nausea, vomiting, and tiredness (lethargy).</p><p>Wilms tumor can develop in one or both kidneys. About 5 to 10 percent of affected individuals develop multiple tumors in one or both kidneys. Wilms tumor may spread from the kidneys to other parts of the body (metastasize). In rare cases, Wilms tumor does not involve the kidneys and occurs instead in the genital tract, bladder, abdomen, chest, or lower back. It is unclear how Wilms tumor develops in these tissues.</p><p>With proper treatment, children with Wilms tumor have a 90 percent survival rate. However, the risk that the cancer will come back (recur) is between 15 and 50 percent, depending on traits of the original tumor. Tumors usually recur in the first 2 years following treatment and develop in the kidneys or other tissues, such as the lungs. Individuals who have had Wilms tumor may experience related health problems or late effects of their treatment in adulthood, such as decreased kidney function, heart disease, and development of additional cancers.</p>", "ghr_link": "https://medlineplus.gov/genetics/condition/wilms-tumor", "db_key_list": [ { "gtr": "C1832099" }, { "gtr": "C1832426" }, { "gtr": "C3887743" }, { "gtr": "C3891301" }, { "gtr": "CN033288" }, { "icd_10_cm": "Z85.528" }, { "mesh": "D009396" }, { "omim": "194070" }, { "omim": "194071" }, { "omim": "194090" }, { "omim": "601363" }, { "omim": "601583" }, { "omim": "616806" }, { "snomed_ct": "25081006" }, { "snomed_ct": "302849000" } ] }, { "name": "Melanoma", "html_text": "<p>Melanoma is a type of skin cancer that begins in pigment-producing cells called melanocytes. This cancer typically occurs in areas that are only occasionally sun-exposed; tumors are most commonly found on the back in men and on the legs in women. Melanoma usually occurs on the skin (cutaneous melanoma), but in about 5 percent of cases it develops in melanocytes in other tissues, including the eyes (uveal melanoma) or mucous membranes that line the body's cavities, such as the moist lining of the mouth (mucosal melanoma). Melanoma can develop at any age, but it most frequently occurs in people in their fifties to seventies and is becoming more common in teenagers and young adults.</p><p>Melanoma may develop from an existing mole or other normal skin growth that becomes cancerous (malignant); however, many melanomas are new growths. Melanomas often have ragged edges and an irregular shape. They can range from a few millimeters to several centimeters across. They can also be a variety of colors: brown, black, red, pink, blue, or white.</p><p>Most melanomas affect only the outermost layer of skin (the epidermis). If a melanoma becomes thicker and involves multiple layers of skin, it can spread to other parts of the body (metastasize).</p><p>A large number of moles or other pigmented skin growths on the body, generally more than 25, is associated with an increased risk of developing melanoma. Melanoma is also a common feature of genetic syndromes affecting the skin such as xeroderma pigmentosum. Additionally, individuals who have previously had melanoma are nearly nine times more likely than the general population to develop melanoma again. It is estimated that about 90 percent of individuals with melanoma survive at least 5 years after being diagnosed.</p>", "ghr_link": "https://medlineplus.gov/genetics/condition/melanoma", "db_key_list": [ { "gtr": "C0025202" }, { "gtr": "C0151779" }, { "gtr": "C1512419" }, { "icd_10_cm": "C43" }, { "mesh": "D008545" }, { "omim": "155600" }, { "omim": "155601" }, { "omim": "608035" }, { "omim": "609048" }, { "omim": "612263" }, { "omim": "613099" }, { "omim": "613972" }, { "omim": "614456" }, { "omim": "615134" }, { "omim": "615848" }, { "snomed_ct": "372244006" }, { "snomed_ct": "830150003" }, { "snomed_ct": "830195005" } ] } ] } ] }, "genomics_england_panelapp": { "version": "10-Nov-2023", "items": [ { "genecolorreview": "Green", "panelid": "245", "genelistname": "Adult_solid_tumours_cancer_susceptibility.PanelApp.20231110", "genelistotherdata": { "types": [ { "name": "Cancer Germline 100K", "description": "Cancer Germline 100K" }, { "name": "GMS Cancer Germline Virtual", "description": "This is a panel used for WGS germline analysis for the GMS." }, { "name": "GMS signed-off", "description": "This panel has undergone review by a NHSE GMS disease specialist group and processes to be signed-off for use within the GMS." } ], "relevant_disorders": [ { "normalized_cancer": "Cancer of Unknown Primary", "name": "Carcinoma of unknown primary", "id": 18446744073709551615 }, { "name": "Other", "id": 18446744073709551615 }, { "normalized_cancer": "Adult Solid Tumours Pertinent Cancer Susceptibility", "name": "Adult solid tumours pertinent cancer susceptibility", "id": 18446744073709551615 } ], "currentversion": "2.27" }, "genelistdescription": "Cancer Programme, Pertinent cancer susceptibility gene panel", "levelofconfidence": "3", "penetrance": "Complete", "modeofinheritance": "MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown", "modeofpathogenicity": null, "evidences": [ "NHS GMS", "Expert Review Green", "Expert list" ], "phenotypes": [ "Li-Fraumeni Syndrome" ], "pub_med_references": null }, { "genecolorreview": "Green", "panelid": "391", "genelistname": "Adult_solid_tumours_for_rare_disease.PanelApp.20231110", "genelistotherdata": { "types": [ { "name": "Rare Disease 100K", "description": "Rare Disease 100K" } ], "relevant_disorders": [ { "normalized_cancer": "Young Adult Onset Cancer", "name": "Young adult onset cancer", "id": 18446744073709551615 }, { "normalized_cancer": "Exceptionally Young Adult Onset Cancer", "name": "Exceptionally young adult onset cancer", "id": 18446744073709551615 }, { "normalized_cancer": "Multiple Tumours", "name": "Multiple Tumours", "id": 18446744073709551615 }, { "normalized_cancer": "Rare Tumour Predisposition Syndromes", "name": "Rare tumour predisposition syndromes", "id": 18446744073709551615 } ], "currentversion": "1.37" }, "genelistdescription": "Tumour syndromes", "levelofconfidence": "3", "penetrance": null, "modeofinheritance": "MONOALLELIC, autosomal or pseudoautosomal, 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[ "Sarcoma" ], "pub_med_references": null }, { "genecolorreview": "Green", "panelid": "734", "genelistname": "Sarcoma_susceptibility.PanelApp.20231110", "genelistotherdata": { "types": [ { "name": "GMS Cancer Germline Virtual", "description": "This is a panel used for WGS germline analysis for the GMS." }, { "name": "GMS signed-off", "description": "This panel has undergone review by a NHSE GMS disease specialist group and processes to be signed-off for use within the GMS." } ], "currentversion": "1.75" }, "genelistdescription": null, "levelofconfidence": "3", "penetrance": null, "modeofinheritance": "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted", "modeofpathogenicity": null, "evidences": [ "Expert Review Green", "NHS GMS" ], "phenotypes": [ "Li-Fraumeni Syndrome, Omim:151623", "Sarcoma, Mondo:0005089" ], "pub_med_references": [ 27050224, 28338660 ] }, { "genecolorreview": "Green", "panelid": "921", "genelistname": "Severe_Paediatric_Disorders.PanelApp.20231110", "genelistotherdata": { "types": [ { "name": "Research", "description": "This is a gene panel used for research." } ], "currentversion": "1.176" }, "genelistdescription": null, "levelofconfidence": "3", "penetrance": null, "modeofinheritance": "MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown", "modeofpathogenicity": null, "evidences": [ "Next Generation Children Project", "Expert Review Green", "Expert list" ], "phenotypes": [ "Bone Marrow Failure Syndrome 5, 618165", "Li-Fraumeni Syndrome, 151623" ], "pub_med_references": [ 30847515 ] } ] }, "transcripts": [ { "name": "NM_000546.6", "strand": "-", "chromo": "chr17", "position": 7571739, "length": 19070, "mrna_length": 2512, "coding_length": 1182, "canonical": null, "cytoband": "17p13.1", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": "ENST00000269305.9", "mane_plus": null, "uniprot_id": null }, { "name": "NM_001126112.3", "strand": "-", "chromo": "chr17", "position": 7571739, "length": 19070, 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null, "cytoband": "17p13.1", "ensembl_support_level": "1", "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "ENST00000505014.1", "strand": "-", "chromo": "chr17", "position": 7577844, "length": 12962, "mrna_length": 1261, "coding_length": null, "canonical": null, "cytoband": "17p13.1", "ensembl_support_level": "2", "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "ENST00000508793.1", "strand": "-", "chromo": "chr17", "position": 7578434, "length": 2319, "mrna_length": 634, "coding_length": 495, "canonical": null, "cytoband": "17p13.1", "ensembl_support_level": "4", "ensembl_appris": "principal1", "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "ENST00000604348.1", "strand": "-", "chromo": "chr17", "position": 7578480, "length": 12326, "mrna_length": 568, "coding_length": 429, "canonical": null, "cytoband": "17p13.1", "ensembl_support_level": "4", "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "ENST00000503591.1", "strand": "-", "chromo": "chr17", "position": 7578547, "length": 12199, "mrna_length": 565, "coding_length": 381, "canonical": null, "cytoband": "17p13.1", "ensembl_support_level": "5", "ensembl_appris": "principal1", "mane_select": null, "mane_plus": null, "uniprot_id": null } ], "weill_cornell_medicine_pmkb": { "version": "08-Feb-2024", "items": [ { "tier": 1, "definition": [ "TP53 copy number loss" ], "interpretations": "TP53 is a well known tumor suppressor gene that is mutated in wide variety of cancers. Loss of function mutations (missense, nonsense and frameshift mutations) of TP53 have been described in 10-20% of CLL cases and TP53 gene defects tend to be enriched among cases with unmutated IGH variable regions; in some series, TP53 mutations have been reported in approximately 15%-18% of IGHV unmutated CLL cases . TP53 mutations appears to be less common in other types of CLL (eg, less than 5% of IGHV3-21-expressing CLL carried a TP53 defect according to one study). Mutations of TP53 in CLL have been found together with del17p and mutations in other genes such as NOTCH1 and SF3B1. Mutations and deletions of TP53 appear to represent adverse prognostic markers in chronic lymphocytic leukemia. ", "tissues": [ "Blood", "Bone Marrow", "Lymph Node" ], "tumour_types": [ "Acute Leukemia of Unspecified Cell Type", "Acute Myeloid Leukemia", "Anemia", "Unspecified", "Atypical Chronic Myeloid Leukemia", "B Lymphoblastic Leukemia/Lymphoma", "Chronic Myeloid Leukemia", "Chronic Myelomonocytic Leukemia", "Chronic Neutrophilic Leukemia", "Cytopenia", "Eosinophilia", "Essential Thrombocythemia", "Histiocytic and Dendritic Cell Neoplasms", "Langerhans Cell Histiocytosis", "Leukocytosis", "Leukopenia", "Mast Cell Neoplasm", "MDS with Ring Sideroblasts", "Monocytosis", "Myelodysplastic Syndrome", "Myelodysplastic/Myeloproliferative Neoplasm", "Myeloproliferative Neoplasm", "Myeloid Neoplasm", "Other Acute Leukemia", "Polycythemia Vera", "Polycythemia", "Primary Myelofibrosis", "T Lymphoblastic Leukemia/Lymphoma", "Thrombocytopenia", "Thrombocytosis" ], "disease_or_trait": null, "pub_med_references": [ 23297687, 23334668, 23403321, 24487413, 24619868, 24652989, 24725250, 24943832 ], "variants": [ { "type": "copy number loss", "gene_id": 33956, "definition": "TP53 copy number loss" } ] }, { "tier": 2, "definition": [ "TP53 any mutation" ], "interpretations": "Somatic mutations in TP53 are frequent in human cancer. Germline TP53 mutations cause of Li-Fraumeni syndrome, which is associated with a range of early-onset cancers. The types and positions of TP53 mutations are diverse. TP53 mutations may be potential prognostic and predictive markers in some tumor types, as well as targets for pharmacological intervention in some clinical settings. The IARC TP53 Database (http://www-p53.iarc.fr/) is a useful resource which catalogues TP53 mutations found in cancer.", "tissues": [ "Skin" ], "tumour_types": [ "Melanoma" ], "disease_or_trait": null, "pub_med_references": null, "variants": [ { "type": "any mutation", "gene_id": 33956, "definition": "TP53 any mutation" } ] }, { "tier": 2, "definition": [ "TP53 any mutation" ], "interpretations": "Somatic mutations in TP53 are frequent in human cancer. Germline TP53 mutations cause of Li-Fraumeni syndrome, which is associated with a range of early-onset cancers. The types and positions of TP53 mutations are diverse. TP53 mutations may be potential prognostic and predictive markers in some tumor types, as well as targets for pharmacological intervention in some clinical settings. The IARC TP53 Database (http://www-p53.iarc.fr/) is a useful resource which catalogues TP53 mutations found in cancer.", "tissues": [ "Colon", "Rectum", "Appendix" ], "tumour_types": [ "Adenocarcinoma" ], "disease_or_trait": null, "pub_med_references": null, "variants": [ { "type": "any mutation", "gene_id": 33956, "definition": "TP53 any mutation" } ] }, { "tier": 2, "definition": [ "TP53 any mutation" ], "interpretations": "Somatic mutations in TP53 are frequent in human cancer. Germline TP53 mutations cause of Li-Fraumeni syndrome, which is associated with a range of early-onset cancers. The types and positions of TP53 mutations are diverse. TP53 mutations may be potential prognostic and predictive markers in some tumor types, as well as targets for pharmacological intervention in some clinical settings. The IARC TP53 Database (http://www-p53.iarc.fr/) is a useful resource which catalogues TP53 mutations found in cancer.", "tissues": [ "Brain" ], "tumour_types": [ "Glioblastoma" ], "disease_or_trait": null, "pub_med_references": null, "variants": [ { "type": "any mutation", "gene_id": 33956, "definition": "TP53 any mutation" } ] }, { "tier": 2, "definition": [ "TP53 copy number loss", "TP53 any deletion" ], "interpretations": "P53 activates the transcription of genes involved in cell cycle arrest, DNA repair, and apoptosis. Deletion and point mutation at the TP53 locus occur in 25%-40% and 5%-40% of prostate cancer, respectively. Although the frequency of p53 mutations seems to be lower in prostate cancer than in other cancers, these alterations are not exclusively late events, as they have been shown in 25% to 30% of clinically localized prostate cancer. Several studies indicate that p53 overexpression may be associated with poor prognosis, especially when present in combination with Bcl2. Interestingly, SPOP mutations are also mutually exclusive with deletions and mutations in the TP53 tumor suppressor.\n", "tissues": [ "Prostate" ], "tumour_types": [ "Adenocarcinoma" ], "disease_or_trait": null, "pub_med_references": null, "variants": [ { "type": "copy number loss", "gene_id": 33956, "definition": "TP53 copy number loss" }, { "type": "any mutation", "gene_id": 33956, "definition": "TP53 any deletion", "coding_impact": "deletion" } ] }, { "tier": 2, "definition": [ "TP53 any mutation" ], "interpretations": "Somatic mutations in TP53 are frequent in human cancer. Germline TP53 mutations cause of Li-Fraumeni syndrome, which is associated with a range of early-onset cancers. The types and positions of TP53 mutations are diverse. TP53 mutations may be potential prognostic and predictive markers in some tumor types, as well as targets for pharmacological intervention in some clinical settings. The IARC TP53 Database (http://www-p53.iarc.fr/) is a useful resource which catalogues TP53 mutations found in cancer.", "tissues": [ "Skin" ], "tumour_types": [ "Langerhans Cell Histiocytosis" ], "disease_or_trait": null, "pub_med_references": null, "variants": [ { "type": "any mutation", "gene_id": 33956, "definition": "TP53 any mutation" } ] }, { "tier": 1, "definition": [ "TP53 copy number loss" ], "interpretations": "TP53 is a well known tumor suppressor gene that is mutated in wide variety of cancers. In terms of myeloid disorders, missense, nonsense, and frameshift mutations of TP53 tend to occur in the DNA binding domain and have been reported in approximately 4% of cases of AML where they tend to be associated with a poorer prognosis and an adverse cytogenetic risk profile. TP53 mutations also occur in approximately 10% of patients with myelodysplastic syndrome (MDS) and are often associated with poorer prognosis, adverse cytogenetic profile and deletion of 5q either in isolation or as part of a complex karyotype. ", "tissues": [ "Blood", "Bone Marrow" ], "tumour_types": [ "Acute Myeloid Leukemia", "Myelodysplastic Syndrome" ], "disease_or_trait": null, "pub_med_references": [ 23297687, 23334668, 23403321, 24487413, 24619868, 24652989, 24725250, 24943832 ], "variants": [ { "type": "copy number loss", "gene_id": 33956, "definition": "TP53 copy number loss" } ] }, { "tier": 1, "definition": [ "TP53 copy number loss" ], "interpretations": " TP53 is a well known tumor suppressor gene that is mutated in wide variety of cancers. Among cases of acute lymphoblastic leukemia, overall TP53 mutations are reported to occur in less than 10% of cases. However, TP53 mutations have a very high prevalence (approximately 90%) among cases of ALL with low hypodiploid karyotype and in this setting are often associated with monosomy 17 and may be associated with germline TP53 mutations in a significant proportion of such cases in children. ", "tissues": [ "Blood", "Bone Marrow" ], "tumour_types": [ "B Lymphoblastic Leukemia/Lymphoma" ], "disease_or_trait": null, "pub_med_references": [ 23297687, 23334668, 23403321, 24487413, 24619868 ], "variants": [ { "type": "copy number loss", "gene_id": 33956, "definition": "TP53 copy number loss" } ] }, { "tier": 2, "definition": [ "TP53 any mutation" ], "interpretations": "Somatic mutations in TP53 are frequent in human cancer. Germline TP53 mutations cause of Li-Fraumeni syndrome, which is associated with a range of early-onset cancers. The types and positions of TP53 mutations are diverse. TP53 mutations may be potential prognostic and predictive markers in some tumor types, as well as targets for pharmacological intervention in some clinical settings. The IARC TP53 Database (http://www-p53.iarc.fr/) is a useful resource which catalogues TP53 mutations found in cancer.", "tissues": [ "Adrenal Gland", "Anus", "Ampulla (Pancreaticobiliary Duct)", "Appendix", "Bladder", "Blood", "Bone", "Bone Marrow", "Brain", "Breast", "Spinal Cord", "Cervix", "Chest Wall", "Endometrium", "Esophagus", "Eye", "Fallopian Tube", "Fibroadipose Tissue", "Gall Bladder", "Kidney", "Larynx", "Liver", "Lung", "Lymph Node", "Nasal Cavity", "Oral Cavity", "Ovary", "Pancreas", "Parathyroid", "Penis", "Peripheral Nervous System", "Peritoneum", "Pharynx", "Pituitary", "Placenta", "Pleura", "Prostate", "Retroperitoneum", "Salivary Gland", "Seminal Vesicle", "Skeletal Muscle", "Skin", "Small Intestine", "Soft Tissue", "Spleen", "Stomach", "Testis", "Thymus", "Thyroid", "Tonsil", "Ureter", "Uterus", "Vagina", "Rectum", "Cartilage", "Blood Vessel", "Buccal Swab", "Heart", "Trachea", "Salivary Duct", "Spermatic Cord", "Vulva", "Infratentorial", "Supratentorial", "Gastroesophageal Junction", "Sellar", "Suprasellar", "Colon" ], "tumour_types": [ "Acinar Cell Carcinoma", "Acinic Cell Carcinoma", "Adenocarcinoma", "Adenoid Cystic Carcinoma", "Adenosarcoma", "Ameloblastic Tumor", "Anaplastic Large Cell Lymphoma", "Angioimmunoblastic T-Cell Lymphoma", "Angiomatoid Fibrous Histiocytoma", "Angiomatosis", "Angiomyolipoma", "Angiosarcoma", "Astrocytoma", "Anaplastic", "Basal Cell Carcinoma", "Burkitt Lymphoma", "Carcinoid Tumor", "Carcinoma", "Carcinosarcoma", "Cholangiocarcinoma", "Chondrosarcoma", "Chordoma", "Choriocarcinoma", "Chromophobe Renal Cell Carcinoma", "Chronic Lymphocytic Leukemia", "Classical Hodgkin Lymphoma", "Clear Cell Carcinoma", "Clear Cell Renal Cell Carcinoma", "Craniopharyngioma", "Dermatofibrosarcoma", "Desmoplastic Small Round Cell Tumor", "Diffuse Large B Cell Lymphoma", "Ductal Carcinoma", "Ependymoma", "Ewing Sarcoma", "Fibromatosis", "Follicular Carcinoma", "Follicular Lymphoma", "Gastrointestinal Stromal Tumor", "Germ Cell Tumor", "Giant Cell Tumor", "Glioblastoma", "Glomus Tumor", "Granular Cell Tumor", "Hairy Cell Leukemia", "Hemangioendothelioma", "Hepatocellular Carcinoma", "Invasive Ductal Carcinoma", "Kaposi Sarcoma", "Leiomyoma", "Leiomyosarcoma", "Lipoma", "Liposarcoma", "Lobular Carcinoma", "Lymphoplasmacytic Lymphoma", "Malignant Mullerian Mixed Tumor", "Mantle Cell Lymphoma", "Marginal Zone B Cell Lymphoma", "Medullary Carcinoma", "Medulloblastoma", "Melanoma", "Meningioma", "Merkel Cell Carcinoma", "Mesothelioma", "Mucinous Adenocarcinoma", "Mucinous Tumors of Ovary", "Mucoepidermoid Carcinoma", "Myxofibrosarcoma", "Nasopharyngeal Carcinoma", "Neuroblastoma", "Neuroendocrine Carcinoma", "Neuroendocrine Neoplasm", "NK Cell Lymphoproliferative Disorder", "NLPHL", "Non-Small Cell Lung Carcinoma", "Oligodendroglioma", "Osteosarcoma", "Papillary Carcinoma", "Papillary Renal Cell Carcinoma", "Peripheral T Cell Lymphoma", "Pheochromocytoma", "Plasma Cell Disorder", "Post-Transplant Lymphoproliferative Disorder", "Primitive Neuroectodermal Tumor", "Renal Cell Carcinoma", "Reninoma", "Retinoblastoma", "Rhabdomyosarcoma", "Sarcoma", "Schwannoma", "Serous Carcinoma", "Sex Cord Stromal Tumor", "Small Cell Carcinoma", "Solid Pseudopapillary Tumor of Pancreas", "Spindle Cell Neoplasm", "Squamous Cell Carcinoma", "T Cell Lymphoproliferative Disorder", "T-Cell LGL Leukemia", "Thymic Carcinoma", "Thymoma", "Urothelial Carcinoma", "Tumors of Peripheral Nerves", "Wilms Tumor", "Pilocytic", "Ganglioglioma", "Neuroepithelial Neoplasm", "NOS", "Pleomorphic Carcinoma", "Solitary Fibrous Tumor", "Neuroepithelial neoplasm", "high grade", "Diffusely Infiltrating", "Diffuse Midline Glioma", "Infiltrating Glioma", "Intraductal Papillary Mucinous Neoplasm (IPMN)", "Lymphadenopathy", "Lymphocytosis", "Symptomatic", "Monoclonal Gammopathy", "Mucinous or Serous Cystic Neoplasms of Pancreas", "Mycosis Fungoides", "Unspecified Site", "Pleomorphic Xanthoastrocytoma", "Rash and Other Nonspecific Skin Eruption" ], "disease_or_trait": null, "pub_med_references": null, "variants": [ { "type": "any mutation", "gene_id": 33956, "definition": "TP53 any mutation" } ] }, { "tier": 1, "definition": [ "TP53 any mutation" ], "interpretations": "TP53 encodes p53, a tumor suppressor protein that consists of transactivation domain, proline-rich domain, DNA-binding domain, oligomerization domain, and regulatory domain. p53 responds to diverse cellular stresses to maintain genomic stability and to induce cell cycle arrest, apoptosis, DNA repair and metabolic changes. TP53 mutations represent an important mechanism of resistance to DNA-damaging chemotherapeutic agents. Somatic TP53 mutations are found in a variety of cancers with various frequencies depending on cancer type; overall, TP53 is mutated in over one-half of human cancers. Missense mutations were the most frequent (~70-80%), followed by frameshift and nonsense mutations. Most TP53 mutations are clustered in the DNA-binding domain encompassing exons 5 and 8. These mutations either directly disrupt the DNA-binding domain of TP53 or cause conformational changes of the TP53 protein, thus leading to severely impaired TP53 function. Overall in myeloid malignancies, TP53 mutations are found in 5% to 15% of de novo MDS and AML but 20% of myelodysplastic syndrome with isolated del(5q) and ~50% of MDS/AML with complex karyotype. TP53 mutations are also more frequent in therapy-associated myeloid neoplasm (21-38%) compared to de novo MDS and AML. TP53 mutations are also found in 8% of blastic plasmacytoid dendritic cell neoplasm, and less than 5% in myeloproliferative neoplasms (ET, PV and PMF) and chronic myelomonocytic leukemia. TP53 mutations are independently associated with a poor prognosis in myelodysplastic syndrome (NCCN Guidelines for Myelodysplastic Syndromes) and is a poor risk factor in AML (NCCN Guildelines for AML). TP53 mutations are also associated with resistance to lenalidomide or relapse during lenalidomide treatment. TP53 mutations are independently associated with unfavorable outcomes and shorter survival after hematopoietic stem cell transplantation in patients with myelodysplastic syndrome and myelodysplastic syndrome/acute myeloid leukemia, but an increased response to decitabine in patients with myelodysplastic syndrome or acute myeloid leukemia.\n\n", "tissues": [ "Blood", "Bone Marrow" ], "tumour_types": [ "Acute Myeloid Leukemia", "Myeloproliferative Neoplasm", "Mast Cell Neoplasm", "Primary Myelofibrosis", "Myelodysplastic Syndrome", "Chronic Myelomonocytic Leukemia", "Acute Leukemia of Unspecified Cell Type", "Anemia", "Unspecified", "Atypical Chronic Myeloid Leukemia", "B Lymphoblastic Leukemia/Lymphoma", "Chronic Myeloid Leukemia", "Chronic Neutrophilic Leukemia", "Cytopenia", "Eosinophilia", "Essential Thrombocythemia", "Histiocytic and Dendritic Cell Neoplasms", "Langerhans Cell Histiocytosis", "Leukocytosis", "Leukopenia", "MDS with Ring Sideroblasts", "Monocytosis", "Myelodysplastic/Myeloproliferative Neoplasm", "Myeloid Neoplasm", "Other Acute Leukemia", "Polycythemia Vera", "Polycythemia", "T Lymphoblastic Leukemia/Lymphoma", "Thrombocytopenia", "Thrombocytosis" ], "disease_or_trait": null, "pub_med_references": [ 23690417, 24072100, 26618142, 27288520, 27601546, 29296692 ], "variants": [ { "type": "any mutation", "gene_id": 33956, "definition": "TP53 any mutation" } ] } ] }, "unil_domino": { "version": "04-Sep-2019", "lda_score": 2.7493300000000005, "numberdonor_numbersynonymous": 0.0, "phylop_at_5_prime_utr": 0.5294619999999999, "probability_of_ad": 0.999028, "string_combined_score": 8, "string_experimental_score": 3, "string_text_mining_score": 3, "mrna_half_life": 0 }, "nih_gtex": { "version": "v8", "items": [ { "exons": [ { "exon_id": "ENSG00000141510.16_1", "exon_number": "1", "end": 7580752, "start": 7580643, "expressions": { "spleen": 0.009090910000000002, "kidney_medulla": 0.004545450000000001, "cells_ebv_transformed_lymphocytes": 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12584563, 21056402, 26014290, 26681312, 28369373 ], "haploinsufficiency_desc": "Sufficient evidence for dosage pathogenicity", "triplosensitivity_desc": "No evidence available", "haploinsufficiency_score": 3, "triplosensitivity_score": 0 }, "protein_atlas": { "version": "14-Mar-2024", "general_info": { "biological_process": "Apoptosis, Biological rhythms, Cell cycle, Host-virus interaction, Necrosis, Transcription, Transcription regulation", "cancer_type": null, "disease_involvement": "Cancer-related genes, Disease variant, Li-Fraumeni syndrome, Tumor suppressor", "hpa_evidence": "Evidence at protein level", "molecular_function": "Activator, DNA-binding, Repressor", "normalized_cancer": null, "protein_class": "Cancer-related genes, Disease related genes, Human disease related genes, Plasma proteins, Potential drug targets, Predicted intracellular proteins, Transcription factors, Transporters", "rna_cancer_distribution": "Detected in all", "rna_cancer_specificity": "Low cancer 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"cancer_name": "head and neck cancer", "high_risk": "1", "low_risk": "0", "medium_risk": "1", "normalized_cancer": "Head and Neck", "not_detected": "2" }, { "cancer_name": "liver cancer", "high_risk": "0", "low_risk": "3", "medium_risk": "0", "normalized_cancer": "Liver", "not_detected": "7" }, { "cancer_name": "lung cancer", "high_risk": "2", "low_risk": "3", "medium_risk": "2", "normalized_cancer": "Lung", "not_detected": "5" }, { "cancer_name": "lymphoma", "high_risk": "0", "low_risk": "3", "medium_risk": "0", "normalized_cancer": "Lymphoma", "not_detected": "9" }, { "cancer_name": "melanoma", "high_risk": "0", "low_risk": "4", "medium_risk": "3", "normalized_cancer": "Melanoma", "not_detected": "4" }, { "cancer_name": "ovarian cancer", "high_risk": "6", "low_risk": "0", "medium_risk": "0", "normalized_cancer": "Ovary/Fallopian Tube", "not_detected": "6" }, { "cancer_name": "pancreatic cancer", "high_risk": "4", "low_risk": "2", "medium_risk": "3", "normalized_cancer": "Pancreas", "not_detected": "1" }, { "cancer_name": "prostate cancer", "high_risk": "0", "low_risk": "0", "medium_risk": "0", "normalized_cancer": "Prostate", "not_detected": "10" }, { "cancer_name": "renal cancer", "high_risk": "0", "low_risk": "1", "medium_risk": "0", "normalized_cancer": "Kidney", "not_detected": "10" }, { "cancer_name": "skin cancer", "high_risk": "1", "low_risk": "5", "medium_risk": "1", "normalized_cancer": "Skin", "not_detected": "4" }, { "cancer_name": "stomach cancer", "high_risk": "5", "low_risk": "2", "medium_risk": "0", "normalized_cancer": "Esophagus/Stomach", "not_detected": "5" }, { "cancer_name": "testis cancer", "high_risk": "1", "low_risk": "7", "medium_risk": "2", "normalized_cancer": "Testis", "not_detected": "2" }, { "cancer_name": "thyroid cancer", "high_risk": "0", "low_risk": "0", "medium_risk": "0", "normalized_cancer": "Thyroid", "not_detected": "4" }, { "cancer_name": "urothelial cancer", "high_risk": "4", "low_risk": "2", "medium_risk": "3", "normalized_cancer": "Bladder/Urinary Tract", "not_detected": "2" } ], "tissue_info": [ { "cell_type": "Adipocytes", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "adipose tissue" }, { "cell_type": "Glandular Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "Adrenal Gland" }, { "cell_type": "Endocrine Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "appendix" }, { "cell_type": "Enterocytes", "level": "Low", "reliability": "Enhanced", "tissue_type": "appendix" }, { "cell_type": "Enterocytes - Microvilli", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "appendix" }, { "cell_type": "Germinal Center Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "appendix" }, { "cell_type": "Goblet Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "appendix" }, { "cell_type": "Non-Germinal Center Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "appendix" }, { "cell_type": "Hematopoietic Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "bone marrow" }, { "cell_type": "Adipocytes", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "Breast" }, { "cell_type": "Glandular Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "Breast" }, { "cell_type": "Myoepithelial Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "Breast" }, { "cell_type": "Respiratory Epithelial Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "bronchus" }, { "cell_type": "Glial Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "caudate" }, { "cell_type": "Neuronal Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "caudate" }, { "cell_type": "Cells In Granular Layer", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "cerebellum" }, { "cell_type": "Cells In Molecular Layer", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "cerebellum" }, { "cell_type": "Purkinje Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "cerebellum" }, { "cell_type": "Endothelial Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "cerebral cortex" }, { "cell_type": "Glial Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "cerebral cortex" }, { "cell_type": "Neuronal Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "cerebral cortex" }, { "cell_type": "Neuropil", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "cerebral cortex" }, { "cell_type": "Glandular Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "Cervix" }, { "cell_type": "Squamous Epithelial Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "Cervix" }, { "cell_type": "Endocrine Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "colon" }, { "cell_type": "Endothelial Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "colon" }, { "cell_type": "Enterocytes", "level": "Medium", "reliability": "Enhanced", "tissue_type": "colon" }, { "cell_type": "Enterocytes - Microvilli", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "colon" }, { "cell_type": "Fibroblasts", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "colon" }, { "cell_type": "Goblet Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "colon" }, { "cell_type": "Mucosal Lymphoid Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "colon" }, { "cell_type": "Peripheral Nerve/Ganglion", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "colon" }, { "cell_type": "Endocrine Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "duodenum" }, { "cell_type": "Enterocytes", "level": "Low", "reliability": "Enhanced", "tissue_type": "duodenum" }, { "cell_type": "Enterocytes - Microvilli", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "duodenum" }, { "cell_type": "Glands Of Brunner", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "duodenum" }, { "cell_type": "Goblet Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "duodenum" }, { "cell_type": "Paneth Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "duodenum" }, { "cell_type": "Cells In Endometrial Stroma", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "endometrium 1" }, { "cell_type": "Glandular Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "endometrium 1" }, { "cell_type": "Cells In Endometrial Stroma", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "endometrium 2" }, { "cell_type": "Glandular Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "endometrium 2" }, { "cell_type": "Glandular Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "epididymis" }, { "cell_type": "Squamous Epithelial Cells", "level": "Medium", "reliability": "Enhanced", "tissue_type": "Esophagus" }, { "cell_type": "Glandular Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "Fallopian Tube" }, { "cell_type": "Glandular Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "gallbladder" }, { "cell_type": "Cardiomyocytes", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "heart muscle" }, { "cell_type": "Glial Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "hippocampus" }, { "cell_type": "Neuronal Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "hippocampus" }, { "cell_type": "Cells In Glomeruli", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "Kidney" }, { "cell_type": "Cells In Tubules", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "Kidney" }, { "cell_type": "Cholangiocytes", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "Liver" }, { "cell_type": "Hepatocytes", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "Liver" }, { "cell_type": "Alveolar Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "Lung" }, { "cell_type": "Macrophages", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "Lung" }, { "cell_type": "Germinal Center Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "lymph node" }, { "cell_type": "Non-Germinal Center Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "lymph node" }, { "cell_type": "Respiratory Epithelial Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "nasopharynx" }, { "cell_type": "Squamous Epithelial Cells", "level": "Medium", "reliability": "Enhanced", "tissue_type": "oral mucosa" }, { "cell_type": "Follicle Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "Ovary" }, { "cell_type": "Ovarian Stroma Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "Ovary" }, { "cell_type": "Exocrine Glandular Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "Pancreas" }, { "cell_type": "Pancreatic Endocrine Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "Pancreas" }, { "cell_type": "Glandular Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "parathyroid gland" }, { "cell_type": "Cytotrophoblasts", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "placenta" }, { "cell_type": "Decidual Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "placenta" }, { "cell_type": "Endothelial Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "placenta" }, { "cell_type": "Hofbauer Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "placenta" }, { "cell_type": "Syncytiotrophoblasts - Cell Body", "level": "Medium", "reliability": "Enhanced", "tissue_type": "placenta" }, { "cell_type": "Syncytiotrophoblasts - Microvilli", "level": "Medium", "reliability": "Enhanced", "tissue_type": "placenta" }, { "cell_type": "Glandular Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "Prostate" }, { "cell_type": "Endocrine Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "rectum" }, { "cell_type": "Endothelial Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "rectum" }, { "cell_type": "Enterocytes", "level": "Medium", "reliability": "Enhanced", "tissue_type": "rectum" }, { "cell_type": "Enterocytes - Microvilli", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "rectum" }, { "cell_type": "Fibroblasts", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "rectum" }, { "cell_type": "Goblet Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "rectum" }, { "cell_type": "Mucosal Lymphoid Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "rectum" }, { "cell_type": "Peripheral Nerve/Ganglion", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "rectum" }, { "cell_type": "Glandular Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "salivary gland" }, { "cell_type": "Glandular Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "seminal vesicle" }, { "cell_type": "Myocytes", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "skeletal muscle" }, { "cell_type": "Fibroblasts", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "skin 1" }, { "cell_type": "Keratinocytes", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "skin 1" }, { "cell_type": "Langerhans", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "skin 1" }, { "cell_type": "Melanocytes", "level": "Low", "reliability": "Enhanced", "tissue_type": "skin 1" }, { "cell_type": "Epidermal Cells", "level": "Low", "reliability": "Enhanced", "tissue_type": "skin 2" }, { "cell_type": "Endocrine Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "small intestine" }, { "cell_type": "Enterocytes", "level": "Low", "reliability": "Enhanced", "tissue_type": "small intestine" }, { "cell_type": "Enterocytes - Microvilli", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "small intestine" }, { "cell_type": "Goblet Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "small intestine" }, { "cell_type": "Paneth Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "small intestine" }, { "cell_type": "Smooth Muscle Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "smooth muscle" }, { "cell_type": "Chondrocytes", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "soft tissue 1" }, { "cell_type": "Fibroblasts", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "soft tissue 1" }, { "cell_type": "Peripheral Nerve", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "soft tissue 1" }, { "cell_type": "Fibroblasts", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "soft tissue 2" }, { "cell_type": "Peripheral Nerve", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "soft tissue 2" }, { "cell_type": "Cells In Red Pulp", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "spleen" }, { "cell_type": "Cells In White Pulp", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "spleen" }, { "cell_type": "Glandular Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "stomach 1" }, { "cell_type": "Glandular Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "stomach 2" }, { "cell_type": "Elongated Or Late Spermatids", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "Testis" }, { "cell_type": "Leydig Cells", "level": "Medium", "reliability": "Enhanced", "tissue_type": "Testis" }, { "cell_type": "Pachytene Spermatocytes", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "Testis" }, { "cell_type": "Peritubular Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "Testis" }, { "cell_type": "Preleptotene Spermatocytes", "level": "Medium", "reliability": "Enhanced", "tissue_type": "Testis" }, { "cell_type": "Round Or Early Spermatids", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "Testis" }, { "cell_type": "Sertoli Cells", "level": "Low", "reliability": "Enhanced", "tissue_type": "Testis" }, { "cell_type": "Spermatogonia Cells", "level": "Medium", "reliability": "Enhanced", "tissue_type": "Testis" }, { "cell_type": "Glandular Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "thyroid gland" }, { "cell_type": "Germinal Center Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "tonsil" }, { "cell_type": "Non-Germinal Center Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "tonsil" }, { "cell_type": "Squamous Epithelial Cells", "level": "Low", "reliability": "Enhanced", "tissue_type": "tonsil" }, { "cell_type": "Urothelial Cells", "level": "Low", "reliability": "Enhanced", "tissue_type": "urinary bladder" }, { "cell_type": "Squamous Epithelial Cells", "level": "Not detected", "reliability": "Enhanced", "tissue_type": "Vagina" } ] }, "saphetor_known_pathogenicity": { "version": "15-Apr-2024", "items": [ { "uncertain": 1811, "totals": [ 753, 249, 1811, 471, 33 ], "total_variants": 3317, "total_frequencies": 0.002647000000000001, "synonymous": [ 5, 2, 34, 330, 22 ], "stoploss": [ 0, 0, 10, 1, 0 ], "start_loss": [ 1, 3, 13, 2, 0 ], "frequency_histogram": { "uncertain": 1811, "pathogenic": 1002, "benign": 504, "buckets": [ { "uncertain": 1635, "to": 4.641999999999999e-6, "pathogenic": 955, "benign": 371, "from": 0.0 }, { "uncertain": 39, "to": 0.00001, "pathogenic": 15, "benign": 29, "from": 4.641999999999999e-6 }, { "uncertain": 10, "to": 0.00002154, "pathogenic": 3, "benign": 6, "from": 0.00001 }, { "uncertain": 31, "to": 0.00004642, "pathogenic": 9, "benign": 23, "from": 0.00002154 }, { "uncertain": 46, "to": 0.00010000000000000003, "pathogenic": 15, "benign": 34, "from": 0.00004642 }, { "uncertain": 24, "to": 0.00021540000000000009, "pathogenic": 3, "benign": 14, "from": 0.00010000000000000003 }, { "uncertain": 12, "to": 0.0004642000000000001, "pathogenic": 2, "benign": 13, "from": 0.00021540000000000009 }, { "uncertain": 9, "to": 0.0010000000000000002, "pathogenic": 0, "benign": 7, "from": 0.0004642000000000001 }, { "uncertain": 0, "to": 0.0021540000000000005, "pathogenic": 0, "benign": 2, "from": 0.0010000000000000002 }, { "uncertain": 2, "to": 0.004642000000000001, "pathogenic": 0, "benign": 1, "from": 0.0021540000000000005 }, { "uncertain": 0, "to": 0.010000000000000002, "pathogenic": 0, "benign": 0, "from": 0.004642000000000001 }, { "uncertain": 2, "to": 0.021540000000000004, "pathogenic": 0, "benign": 0, "from": 0.010000000000000002 }, { "uncertain": 0, "to": 0.04642000000000001, "pathogenic": 0, "benign": 3, "from": 0.021540000000000004 }, { "uncertain": 0, "to": 0.1, "pathogenic": 0, "benign": 0, "from": 0.04642000000000001 }, { "uncertain": 0, "to": 0.21540000000000004, "pathogenic": 0, "benign": 0, "from": 0.1 }, { "uncertain": 0, "to": 0.4642, "pathogenic": 0, "benign": 0, "from": 0.21540000000000004 }, { "uncertain": 1, "to": 1.0, "pathogenic": 0, "benign": 1, "from": 0.4642 } ] }, "pathogenic": 1002, "splice_junction_loss": [ 73, 45, 23, 5, 2 ], "frequency_benign_threshold": 0.0004355000000000002, "gene_id": 33956, "frameshift": [ 335, 41, 83, 0, 0 ], "benign": 504, "exon_deletion": [ 0, 0, 0, 0, 0 ], "gene_symbol": "TP53", "in_frame": [ 15, 24, 82, 1, 0 ], "missense": [ 218, 119, 1449, 62, 4 ], "most_common_pathogenic_variant": "chr17-7578456-G-A", "most_common_pathogenic_variant_ethnicity": "African", "nonsense": [ 105, 11, 12, 3, 1 ], "most_common_pathogenic_variant_frequency": 0.0004312000000000002, "frequency_pathogenic_total": 0.002647000000000001, "non_coding": [ 1, 4, 105, 67, 4 ] } ] }, "ebi_gene_2_phenotype": { "version": "07-Jun-2022", "items": [ { "disease": "Li-Fraumeni Syndrome", "verdict": "definitive", "expert_panel": "Cancer", "inheritance": "monoallelic_autosomal", "organs": null, "pub_med_references": [ "1565143", "1565144", "1644930", "1679237", "1683921", "1933902", "1978757", "2259385", "8118819", "8134127", "8649785", "9569035", "10484981", "15977174" ] }, { "disease": "Adrenal Cortical Carcinoma", "verdict": "strong", "expert_panel": "Cancer", "inheritance": "biallelic_autosomal", "organs": null, "pub_med_references": [ "11481490", "18762572" ] }, { "disease": "Choroid Plexus Papilloma", "verdict": "limited", "expert_panel": "Cancer", "inheritance": "biallelic_autosomal", "organs": null, "pub_med_references": [ "12085209" ] } ] }, "gen_cc": { "version": "05-Jan-2024", "items": [ { "disease": "Sarcoma", "verdict": "Strong", "expert_panel": "Genomics England PanelApp", "inheritance": "Autosomal dominant", "pub_med_references": [ "27050224", "28338660" ] }, { "disease": "Li-Fraumeni Syndrome 1", "verdict": "Strong", "expert_panel": "Genomics England PanelApp", "inheritance": "Autosomal dominant", "pub_med_references": null }, { "disease": "Li-Fraumeni Syndrome", "verdict": "Strong", "expert_panel": "Invitae", "inheritance": "Autosomal dominant", "pub_med_references": [ "191170", "1642235", "3480372", "9006316", "9039259", "9242456", "9554443", "10864200", "12826609", "20522432", "21343334", "21941372", "22275381", "26086041", "27496084", "28135145", "28649662", "29146522", "29478780", "29522266", "30287823", "30730459", "31105275", "32998877" ] }, { "disease": "Li-Fraumeni Syndrome", "verdict": "Supportive", "expert_panel": "Orphanet", "inheritance": "Autosomal dominant", "pub_med_references": [ "20301488" ] }, { "disease": "Choroid Plexus Carcinoma", "verdict": "Supportive", "expert_panel": "Orphanet", "inheritance": "Autosomal dominant", "pub_med_references": [ "21445348" ] }, { "disease": "Breast Cancer", "verdict": "Definitive", "expert_panel": "Ambry Genetics", "inheritance": "Autosomal dominant", "pub_med_references": [ "28106320" ] }, { "disease": "Li-Fraumeni Syndrome 1", "verdict": "Definitive", "expert_panel": "Ambry Genetics", "inheritance": "Autosomal dominant", "pub_med_references": [ "28106320" ] }, { "disease": "Adrenocortical Carcinoma, Hereditary", "verdict": "Strong", "expert_panel": "Ambry Genetics", "inheritance": "Autosomal dominant", "pub_med_references": [ "28106320" ] }, { "disease": "Bone Marrow Failure Syndrome 5", "verdict": "Limited", "expert_panel": "Ambry Genetics", "inheritance": "Autosomal dominant", "pub_med_references": [ "28106320" ] }, { "disease": "Familial Ovarian Cancer", "verdict": "Limited", "expert_panel": "ClinGen", "inheritance": "Autosomal dominant", "pub_med_references": null }, { "disease": "Li-Fraumeni Syndrome 1", "verdict": "Definitive", "expert_panel": "ClinGen", "inheritance": "Autosomal dominant", "pub_med_references": null }, { "disease": "Li-Fraumeni Syndrome", "verdict": "Definitive", "expert_panel": "TGMI G2P", "inheritance": "Autosomal dominant", "pub_med_references": [ "1565143", "1565144", "1644930", "1679237", "1683921", "1933902", "1978757", "2259385", "8118819", "8134127", "8649785", "9569035", "10484981", "15977174" ] } ] }, "nih_clin_gen_disease_validity": { "version": "08-Feb-2024", "items": [ { "disease": "Familial Ovarian Cancer", "verdict": "Limited", "expert_panel": "Breast/Ovarian Cancer" }, { "disease": "Li-Fraumeni Syndrome 1", "verdict": "Definitive", "expert_panel": "Hereditary Cancer" } ] } }