Variant Annotation
Available parameters and response documentation is available here
GET /lookup/TP53:R273H?add-AMP-annotation=1&format=api
{ "chromosome": "chr17", "alt": "T", "ref": "C", "pos": 7577120, "variant_id": "10190170075771200004", "regions": { "uniprot_regions": { "version": "08-Dec-2023", "items": [ { "absolute_positon": 1076661183, "amino_acid": "M1-L25,L25-L32,S33-T125,Y126-G187,G187-E224,V225-S261,S261-A307,A307-Q331,I332-S367,S367-D393", "chromo": "chr17", "colour": "255,0,0", "description": null, "length": 19067, "position": 7571739, "protein": "P53_HUMAN", "type": "homo_sapiens proteome sequences", "pub_med_references": null }, { "absolute_positon": 1076661183, "amino_acid": "M1-L25,L25-L32,S33-T125,Y126-G187,G187-E224,V225-S261,S261-A307,A307-Q331,I332-S367,S367-D393", "chromo": "chr17", "colour": "255,0,0", "description": null, "length": 19070, "position": 7571739, "protein": "P53_HUMAN", "type": "homo_sapiens proteome sequences", "pub_med_references": null }, { "absolute_positon": 1076662443, "amino_acid": "Q100-K370", "chromo": "chr17", "colour": "255,102,0", "description": "Interaction with HIPK1", "length": 6391, "position": 7572999, "protein": "P53_HUMAN", "type": "region of interest", "pub_med_references": null }, { "absolute_positon": 1076666330, "amino_acid": "M1-K320", "chromo": "chr17", "colour": "255,102,0", "description": "Interaction with CCAR2", "length": 3027, "position": 7576886, "protein": "P53_HUMAN", "type": "region of interest", "pub_med_references": null }, { "absolute_positon": 1076666482, "amino_acid": "Q100-P300", "chromo": "chr17", "colour": "255,102,0", "description": "Required for interaction with ZNF385A", "length": 2352, "position": 7577038, "protein": "P53_HUMAN", "type": "region of interest", "pub_med_references": null }, { "absolute_positon": 1076666500, "amino_acid": "T256-E294", "chromo": "chr17", "colour": "255,102,0", "description": "Interaction with E4F1", "length": 460, "position": 7577056, "protein": "P53_HUMAN", "type": "region of interest", "pub_med_references": null }, { "absolute_positon": 1076666506, "amino_acid": "S116-K292", "chromo": "chr17", "colour": "255,102,0", "description": "Interaction with AXIN1", "length": 2280, "position": 7577062, "protein": "P53_HUMAN", "type": "region of interest", "pub_med_references": null }, { "absolute_positon": 1076666506, "amino_acid": "T102-K292", "chromo": "chr17", "colour": "0,153,51", "description": "DNA-binding region_102-292", "length": 2322, "position": 7577062, "protein": "P53_HUMAN", "type": "DNA-binding domain", "pub_med_references": null }, { "absolute_positon": 1076666542, "amino_acid": "R273-R280", "chromo": "chr17", "colour": "255,102,0", "description": "Interaction with DNA", "length": 24, "position": 7577098, "protein": "P53_HUMAN", "type": "region of interest", "pub_med_references": null } ] }, "nih_gtex": { "version": "v8", "items": [ { "GTExJsonData": { "exon_id": "ENSG00000141510.16_7", "exon_number": "7", "expressions": { "adipose_subcutaneous": 1.00077, "adipose_visceral_omentum": 0.838552, "adrenal_gland": 0.6820020000000001, "artery_aorta": 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0.6170760000000001, "esophagus_mucosa": 1.14474, "esophagus_muscularis": 0.536784, "fallopian_tube": 0.907222, "heart_atrial_appendage": 0.35228600000000004, "heart_left_ventricle": 0.26335000000000003, "kidney_cortex": 0.394737, "kidney_medulla": 0.7093740000000001, "liver": 0.296197, "lung": 0.6229350000000001, "minor_salivary_gland": 0.9606460000000001, "muscle_skeletal": 0.34056900000000007, "nerve_tibial": 0.848156, "ovary": 1.10353, "pancreas": 0.443767, "pituitary": 0.32462500000000005, "prostate": 0.7127350000000001, "skin_not_sun_exposed_suprapubic": 1.49155, "skin_sun_exposed_lower_leg": 1.59787, "small_intestine_terminal_ileum": 0.863523, "spleen": 1.00307, "stomach": 0.5875910000000001, "testis": 0.586439, "thyroid": 0.6786400000000002, "uterus": 1.0178599999999998, "vagina": 0.939397, "whole_blood": 0.4008840000000001 }, "gencode_id": "ENSG00000141510", "gene": "TP53", "gene_model_positions": { "chromosome": "chr17", "end": 7580752, "start": 7565097, "strand": "-" }, "gene_positions": { "chromosome": "chr17", "end": 7590868, "start": 7565097, "strand": "-" } }, "absolute_positon": 1076666464, "chromo": "chr17", "length": 136, "position": 7577020 } ] } }, "variant_type": "SNV", "cytobands": "17p13.1", "refseq_transcripts": [ { "items": [ { "name": "NM_000546.6", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.818G>A", "hgvs_p1": "R273H", "hgvs_p3": "p.(Arg273His)", "location": "exon 8 of 11 position 36 of 137", "coding_location": "273 of 394", "canonical": false, "gene_symbol": "TP53", "splice_distance": "36", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": "ENST00000269305.9", "mane_plus": null, "uniprot_id": null }, { "name": "NM_001126112.3", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.818G>A", "hgvs_p1": "R273H", "hgvs_p3": "p.(Arg273His)", "location": "exon 8 of 11 position 36 of 137", "coding_location": "273 of 394", "canonical": false, "gene_symbol": "TP53", "splice_distance": "36", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001126113.3", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.818G>A", "hgvs_p1": "R273H", "hgvs_p3": "p.(Arg273His)", "location": "exon 8 of 12 position 36 of 137", "coding_location": "273 of 347", "canonical": false, "gene_symbol": "TP53", "splice_distance": "36", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001126114.3", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.818G>A", "hgvs_p1": "R273H", "hgvs_p3": "p.(Arg273His)", "location": "exon 8 of 12 position 36 of 137", "coding_location": "273 of 342", "canonical": false, "gene_symbol": "TP53", "splice_distance": "36", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001126115.2", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.422G>A", "hgvs_p1": "R141H", "hgvs_p3": "p.(Arg141His)", "location": "exon 4 of 7 position 36 of 137", "coding_location": "141 of 262", "canonical": false, "gene_symbol": "TP53", "splice_distance": "36", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001126116.2", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.422G>A", "hgvs_p1": "R141H", "hgvs_p3": "p.(Arg141His)", "location": "exon 4 of 8 position 36 of 137", "coding_location": "141 of 210", "canonical": false, "gene_symbol": "TP53", "splice_distance": "36", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001126117.2", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.422G>A", "hgvs_p1": "R141H", "hgvs_p3": "p.(Arg141His)", "location": "exon 4 of 8 position 36 of 137", "coding_location": "141 of 215", "canonical": false, "gene_symbol": "TP53", "splice_distance": "36", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001126118.2", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.701G>A", "hgvs_p1": "R234H", "hgvs_p3": "p.(Arg234His)", "location": "exon 7 of 10 position 36 of 137", "coding_location": "234 of 355", "canonical": false, "gene_symbol": "TP53", "splice_distance": "36", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001276695.3", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.701G>A", "hgvs_p1": "R234H", "hgvs_p3": "p.(Arg234His)", "location": "exon 8 of 12 position 36 of 137", "coding_location": "234 of 308", 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null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001276698.3", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.341G>A", "hgvs_p1": "R114H", "hgvs_p3": "p.(Arg114His)", "location": "exon 4 of 8 position 36 of 137", "coding_location": "114 of 183", "canonical": false, "gene_symbol": "TP53", "splice_distance": "36", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001276699.3", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.341G>A", "hgvs_p1": "R114H", "hgvs_p3": "p.(Arg114His)", "location": "exon 4 of 8 position 36 of 137", "coding_location": "114 of 188", "canonical": false, "gene_symbol": "TP53", "splice_distance": "36", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001276760.3", "strand": "-", "coding_impact": "missense", "function": [ 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null, "uniprot_id": "P04637" }, { "name": "ENST00000455263.2", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.818G>A", "hgvs_p1": "R273H", "hgvs_p3": "p.(Arg273His)", "location": "exon 8 of 12 position 36 of 137", "coding_location": "273 of 347", "canonical": false, "gene_symbol": "TP53", "splice_distance": "36", "ensembl_support_level": "1", "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": "P04637" }, { "name": "ENST00000504290.1", "strand": "-", "coding_impact": null, "function": [ "non-coding exon" ], "hgvs": null, "hgvs_p1": null, "hgvs_p3": null, "location": "exon 4 of 8 position 36 of 137", "coding_location": null, "canonical": false, "gene_symbol": "TP53", "splice_distance": "36", "ensembl_support_level": "1", "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "ENST00000504937.1", "strand": "-", "coding_impact": null, "function": [ "non-coding exon" ], "hgvs": null, 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"coding_impact": null, "function": [ "5'flank" ], "hgvs": null, "hgvs_p1": "p.?", "hgvs_p3": "p.?", "location": "215 bp before transcription start site", "coding_location": null, "canonical": false, "gene_symbol": "TP53", "splice_distance": null, "ensembl_support_level": "1", "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null } ], "version": "110" } ], "gnomad_exomes": [ { "version": "2.1.1", "filter": "PASS", "ac": 4, "an": 251054, "af": 0.000015932827200522597, "ac_asj": 1, "ac_nfe": 3, "ac_nfe_nwe": 2, "ac_nfe_seu": 1, "ac_asj_male": 1, "ac_nfe_male": 2, "ac_nfe_female": 1, "ac_male": 3, "ac_female": 1, "an_afr": 16232, "an_amr": 34526, "an_asj": 10072, "an_eas": 18382, "an_eas_kor": 3816, "an_eas_jpn": 152, "an_eas_oea": 14414, "an_fin": 21616, "an_nfe": 113520, "an_nfe_bgr": 2668, "an_nfe_est": 242, "an_nfe_nwe": 42164, "an_nfe_onf": 30902, "an_nfe_seu": 11492, "an_nfe_swe": 26052, "an_oth": 6122, "an_sas": 30584, "an_afr_male": 6174, "an_amr_male": 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16401470, 16489069, 17540308, 17606709, 17636407, 18511570, 19454241, 20128691, 20516128, 20693561, 21343334, 21552135, 21761402, 22811390, 22899716, 23161690, 24381225, 24487413, 24641375, 24677579, 25157968, 25584008, 25787918, 26332594, 26619011, 26681312, 27374712, 28453743, 28873162, 29489754, 29979965, 30224644, 30816478, 31882575, 33372952, 36988593 ], "clinical_significance": [ "Pathogenic" ], "last_evaluation": "20240126", "origin": null, "accessions": [ { "variation_id": 12366, "accession_id": "RCV000254693", "diseases": [ { "symbols": { "medgen": "C3661900" }, "names": [ "Not Provided", "None Provided" ] } ], "allele_id": 27405, "clinical_significance": [ "Pathogenic" ], "submissions": [ { "submitter_name": "Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital", "submission_description": [], "submitter_date": 20230816, "review_description": "Pathogenic", "review_status": "criteria provided, single submitter", "review_date": 20230815, "origin": "germline", "method": "clinical testing", "date_updated": 20230819, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "names": [ "Not Provided" ] } ], "accession_id": "SCV004026686" }, { "submitter_name": "GeneDx", "submission_description": [ "Not observed at a significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity (Kato 2003, Monti 2011, Wasserman 2015, Kotler 2018); This variant is associated with the following publications: (PMID: 23334668, 20128691, 7732013, 10864200, 18511570, 25896519, 23484829, 29324801, 32039725, 15492269, 17606709, 22811390, 23559009, 22899716, 24573247, 24677579, 25958320, 26703669, 17636407, 25433984, 26332594, 8423216, 20693561, 21054160, 1565144, 21552135, 21484931, 25584008, 23172776, 17540308, 27798748, 25530302, 27498048, 27323394, 27287813, 27346245, 27659839, 27374712, 28091804, 27501770, 25787918, 1447251, 9242456, 12672316, 16401470, 28509937, 20522432, 27831900, 26225655, 26681312, 28453743, 21761402, 16096528, 29489754, 28472496, 21343334, 26585234, 28861920, 29752822, 15607980, 30287823, 30720243, 30092803, 30840781, 31159747, 15951970, 22851211, 28369373, 31105275, 32475984, 32156018, 33300245, 34308366, 32817165, 33372952, 31958074, 33332384, 33245408, 32427313, 33087929, 33144694, 29979965, 15510160)" ], "submitter_date": 20220525, "review_description": "Pathogenic", "review_status": "criteria provided, single submitter", "review_date": 20220429, "origin": "germline", "method": "clinical testing", "date_updated": 20230304, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "names": [ "Not Provided" ] } ], "accession_id": "SCV000149647" }, { "submitter_name": "Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen", "submission_description": [], "submitter_date": 20210617, "review_description": "Pathogenic", "review_status": "criteria provided, single submitter", "review_date": 20210617, "origin": "germline", "method": "clinical testing", "finding": [ { "symbols": { "hp": "HP:0003002" }, "normalized_phenotype": [ "Breast Carcinoma" ] } ], "date_updated": 20210731, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "names": [ "Not Provided" ] } ], "accession_id": "SCV001762058" }, { "submitter_name": "ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories", "submission_description": [ "The TP53 c.818G>A, p.Arg273His variant (rs28934576), has been reported in multiple patients diagnosed with Li-Fraumeni syndrome (Curry 2011, Khayat 2004, Malkin 1992, Park 2016, Schlegelberger 2015, Siddiqui 2005, Tsaousis 2019, Zerdoumi 2012). Functional characterization of the variant protein indicates a defect in the transactivation of TP53 targets (Malcikova 2010, Monti 2007, Monti 2011, Zerdoumi 2012) and repression of genes involved in cell proliferation (Scian 2004). This results in an increase in growth, invasiveness, and resistance to apoptosis of cell lines upon DNA damage (Kalo 2012, Li 2014). This variant is found in the general population with an allele frequency of 0.0016% (4/251054 alleles) in the Genome Aggregation Database. The arginine at residue 273 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.868). Based on the above information, the variant is classified as pathogenic. References: Curry S et al. Rhabdomyosarcoma-associated renal cell carcinoma: a link with constitutional Tp53 mutation. Pediatr Dev Pathol. 2011; 14(3):248-51. Kalo E et al. Mutant p53R273H attenuates the expression of phase 2 detoxifying enzymes and promotes the survival of cells with high levels of reactive oxygen species. J Cell Sci. 2012; 125(Pt 22):5578-86. Khayat C et al. Rhabdomyosarcoma, osteosarcoma, and adrenocortical carcinoma in a child with a germline p53 mutation. Pediatr Blood Cancer. 2004; 43(6):683-6. Li J et al. Mutants TP53 p.R273H and p.R273C but not p.R273G enhance cancer cell malignancy. Hum Mutat. 2014; 35(5):575-84. Malcikova J et al. Analysis of the DNA-binding activity of p53 mutants using functional protein microarrays and its relationship to transcriptional activation. Biol Chem. 2010; 391(2-3):197-205. Malkin D et al. Germline mutations of the p53 tumor-suppressor gene in children and young adults with second malignant neoplasms. N Engl J Med. 1992; 326(20):1309-15. Monti P et al. Transcriptional functionality of germ line p53 mutants influences cancer phenotype. Clin Cancer Res. 2007; 13(13):3789-95. Monti P et al. Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes. Mol Cancer Res. 2011; 9(3):271-9. Schlegelberger B et al. A child with Li-Fraumeni syndrome: Modes to inactivate the second allele of TP53 in three different malignancies. Pediatr Blood Cancer. 2015; 62(8):1481-4. Scian M et al. Modulation of gene expression by tumor-derived p53 mutants. Cancer Res. 2004; 64(20):7447-54. Siddiqui R et al. The TP53 mutational spectrum and frequency of CHEK2*1100delC in Li-Fraumeni-like kindreds. Fam Cancer. 2005; 4(2):177-81. Tsaousis GN et al. Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. BMC Cancer. 2019 Jun 3;19(1):535. Zerdoumi Y et al. Drastic effect of germline TP53 missense mutations in Li-Fraumeni patients. Hum Mutat. 2013; 34(3):453-61." ], "submitter_date": 20220104, "review_description": "Pathogenic", "review_status": "criteria provided, single submitter", "review_date": 20210318, "origin": "germline", "method": "clinical testing", "finding": [ { "symbols": { "medgen": "CN235283" } } ], "date_updated": 20220108, "clinical_significance": [ "Pathogenic" ], "accession_id": "SCV000605425" }, { "submitter_name": "Genetic Services Laboratory, University of Chicago", "submission_description": [ "DNA sequence analysis of the TP53 gene demonstrated a sequence change, c.818G>A, in exon 8 that results in an amino acid change, p.Arg273His. This sequence change has been described in the gnomAD database with a low global population frequency of 0.01% (dbSNP rs28934576). This pathogenic sequence change has previously been described in multiple patients and families with Li Fraumeni syndrome (PMIDs: 1565144, 21054160, 25584008). The p.Arg273His change affects a highly conserved amino acid residue located in a domain of the TP53 protein that is known to be functional. The p.Arg273 amino acid residue has multiple other amino acid substitutions that are reported to be pathogenic, including p.Arg273Leu, p.Arg273Gly, p.Arg273Ser, and p.Arg273Cys (PMIDs: 10864200, 8425176, 8164043, 8479749). Functional assays demonstrate that the p.Arg273His change results in deficient transactivation activity and results in a dominant negative effect over wild-type p53 (PMIDs: 12826609, 17636407). The p.Arg273His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL)." ], "submitter_date": 20220125, "review_description": "Pathogenic", "review_status": "criteria provided, single submitter", "review_date": 20190403, "origin": "germline", "method": "clinical testing", "date_updated": 20220129, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "names": [ "Not Provided" ] } ], "accession_id": "SCV002072052" }, { "submitter_name": "Quest Diagnostics Nichols Institute San Juan Capistrano", "submission_description": [], "submitter_date": 20170801, "review_description": "Pathogenic", "review_status": "criteria provided, single submitter", "review_date": 20170426, "origin": "germline", "method": "clinical testing", "date_updated": 20220101, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "names": [ "Not Provided" ] } ], "accession_id": "SCV000602280" }, { "submitter_name": "Mayo Clinic Laboratories, Mayo Clinic", "submission_description": [], "submitter_date": 20171031, "review_description": "Pathogenic", "review_status": "no assertion criteria provided", "origin": "unknown", "method": "clinical testing", "date_updated": 20180219, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "names": [ "Not Provided" ] } ], "accession_id": "SCV000692068" } ], "date_created": 20161028, "review_date": 20230815, "review_status": "criteria provided, multiple submitters, no conflicts", "review_description": "Pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND not provided", "review_stars": 2, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV003466853", "diseases": [ { "normalized_disease": [ "Adrenocortical Carcinoma, Hereditary" ], "symbols": { "orphanet": "1501", "omim": "202300", "medgen": "C1859972", "mondo": "MONDO:0008734" }, "normalized_cancer": [ "Adrenocortical Carcinoma" ], "names": [ "Adrenocortical Carcinoma, Hereditary" ], "keyword": "Hereditary cancer syndrome" } ], "allele_id": 27405, "clinical_significance": [ "Pathogenic" ], "submissions": [ { "submitter_name": "Baylor Genetics", "submission_description": [], "submitter_date": 20231207, "review_description": "Pathogenic", "review_status": "criteria provided, single submitter", "review_date": 20230719, "origin": "unknown", "method": "clinical testing", "date_updated": 20231230, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "symbols": { "omim": "202300" } } ], "accession_id": "SCV004206253" } ], "date_created": 20231230, "review_date": 20230719, "review_status": "criteria provided, single submitter", "review_description": "Pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Adrenocortical carcinoma, hereditary", "review_stars": 1, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "variant_id": 10190170075771200004, "accession_id": "RCV000013163", "diseases": [ { "pub_med": [ 17392385, 20065170, 12692171, 15604628, 23788249, 24493721, 25394175, 25356965, 26389258, 26324357 ], "normalized_disease": [ "Li-Fraumeni Syndrome" ], "symbols": { "orphanet": "524", "omim": "151623", "medgen": "C1835398", "gene": "553989" }, "names": [ "Li-Fraumeni Syndrome" ] } ], "allele_id": 27405, "clinical_significance": [ "Pathogenic", "Likely pathogenic" ], "submissions": [ { "submitter_name": "Myriad Genetics, Inc.", "submission_description": [ "This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9399838]. Functional studies indicate this variant impacts protein function [PMID: 1631137, 14743206, 19454241, 24677579]. This variant is expected to disrupt protein structure [PMID: 24677579, Myriad internal data]." ], "submitter_date": 20231023, "review_description": "Pathogenic", "review_status": "criteria provided, single submitter", "review_date": 20230511, "origin": "unknown", "method": "clinical testing", "date_updated": 20231028, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "symbols": { "omim": "151623" } } ], "accession_id": "SCV004043518" }, { "submitter_name": "3billion", "submission_description": [ "The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12826609 , 30224644). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.87; 3Cnet: 1.00). The variant has been previously reported as de novo in a similarly affected individual (PMID: 12672316). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10864200 , 15390294 , 1565144 , 16401470 , 7732013 , 9242456). Different missense changes at the same codon (p.Arg273Cys, p.Arg273Gly, p.Arg273Leu, p.Arg273Pro, p.Arg273Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000043594 , VCV000231060 , VCV000376655 , VCV000376656 , VCV000634682). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline." ], "submitter_date": 20220904, "review_description": "Pathogenic", "review_status": "criteria provided, single submitter", "review_date": 20220901, "origin": "germline", "method": "clinical testing", "finding": [ { "symbols": { "hp": "HP:0002669" }, "normalized_phenotype": [ "Osteosarcoma" ] } ], "date_updated": 20220917, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "symbols": { "omim": "151623" } } ], "accession_id": "SCV002572762" }, { "submitter_name": "Centogene AG - the Rare Disease Company", "submission_description": [], "submitter_date": 20211221, "review_description": "Pathogenic", "review_status": "criteria provided, single submitter", "review_date": 20211123, "origin": "germline", "method": "clinical testing", "date_updated": 20220115, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "symbols": { "omim": "151623" } } ], "accession_id": "SCV002059231" }, { "submitter_name": "New York Genome Center", "submission_description": [ "The c.818G>A, p.Arg273His missense variant in TP53 has been reported in several individuals meeting classic Li-Fraumeni or Chompret criteria,occurring de novo in at least one individual and segregating with disease in affected families (PMID: 9242456, 21484931, 17540308, 1565144, 20693561, 21552135). This variant is located in the DNA-binding domain of the TP53 protein and is defined as a contact mutation that eliminates an essential DNA contact (PMID: 20516128). A mutant mouse model for this variant develops various tumors and carcinomas by recapitulating LFS (PMID: 15607980). In addition, experimental studies have shown that this variant disrupts transcriptional activity in yeast-based assays (PMID: 12826609) and enhances cell proliferation, invasion, migration, and drug resistance in vitro (PMID:17636407, 24677579). This variant has three heterozygous alleles in the gnomAD v3.1.1 database, suggesting it is not a common benign variant in the populations represented in this database. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, this variant is classified as pathogenic." ], "submitter_date": 20221205, "review_description": "Pathogenic", "review_status": "criteria provided, single submitter", "review_date": 20210910, "origin": "germline", "method": "clinical testing", "finding": [ { "symbols": { "hp": "HP:0001397" }, "normalized_phenotype": [ "Hepatic Steatosis" ] }, { "symbols": { "hp": "HP:0005978" }, "normalized_phenotype": [ "Type Ii Diabetes Mellitus" ] }, { "symbols": { "hp": "HP:0003077" }, "normalized_phenotype": [ "Hyperlipidemia" ] } ], "date_updated": 20221217, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "symbols": { "omim": "151623" } } ], "accession_id": "SCV002764339" }, { "submitter_name": "Department of Pediatrics, Memorial Sloan Kettering Cancer Center", "submission_description": [], "submitter_date": 20201216, "review_description": "Pathogenic", "review_status": "criteria provided, single submitter", "review_date": 20201215, "origin": "germline", "method": "research", "date_updated": 20210619, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "symbols": { "omim": "151623" } } ], "accession_id": "SCV001478190" }, { "submitter_name": "Counsyl", "submission_description": [], "submitter_date": 20170622, "review_description": "Likely pathogenic", "review_status": "criteria provided, single submitter", "review_date": 20170222, "origin": "unknown", "method": "clinical testing", "date_updated": 20221224, "clinical_significance": [ "Likely pathogenic" ], "diseases": [ { "symbols": { "omim": "151623" } } ], "accession_id": "SCV000677727" }, { "submitter_name": "Pathway Genomics", "submission_description": [], "submitter_date": 20140808, "review_description": "Pathogenic", "review_status": "no assertion criteria provided", "review_date": 20140724, "origin": "germline", "method": "clinical testing", "date_updated": 20141019, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "normalized_disease": [ "Li-Fraumeni Syndrome" ], "symbols": { "omim": "151623" }, "names": [ "Li-Fraumeni Syndrome" ] } ], "accession_id": "SCV000190004" }, { "submitter_name": "OMIM", "submission_description": [ "Malkin et al. (1992) identified a germline CGT-to-CAT mutation in exon 8 of the p53 gene that converted arg273 to his (R273H). The proband was a male in whom soft-tissue sarcoma was discovered at the age of 22 years and gastric carcinoma at the age of 30 years (see LFS; 151623).", "In 5 of 6 anaplastic carcinomas of the thyroid and in an anaplastic carcinoma thyroid cell line ARO, Fagin et al. (1993) identified the R273H mutation. The presence of p53 mutations almost exclusively in poorly differentiated thyroid tumors and thyroid cancer cell lines suggested that inactivation of p53 may confer these neoplasms with aggressive properties and may further loss of differentiated function." ], "submitter_date": 20130409, "review_description": "Pathogenic", "review_status": "no assertion criteria provided", "review_date": 19930101, "origin": "germline", "pub_med_references": [ 1565144, 8423216 ], "method": "literature only", "date_updated": 20130408, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "normalized_disease": [ "Li-Fraumeni Syndrome" ], "names": [ "Li-Fraumeni Syndrome" ] } ], "accession_id": "SCV000033410" } ], "date_created": 20130404, "review_date": 20230511, "review_status": "criteria provided, multiple submitters, no conflicts", "pub_med_references": [ 1565144, 8423216 ], "review_description": "Pathogenic/Likely pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Li-Fraumeni syndrome 1", "review_stars": 2, "submission_description": [] }, { "variation_id": 12366, "accession_id": "RCV000431361", "diseases": [ { "pub_med": [ 23562183, 25311215, 24627688, 29355391, 29398453 ], "normalized_disease": [ "Lung Adenocarcinoma", "Lung Cancer" ], "symbols": { "medgen": "C0152013", "mesh": "D000077192", "mondo": "MONDO:0005061", "human_phenotype_ontology": "HP:0030078" }, "normalized_cancer": [ "Lung Adenocarcinoma In Situ" ], "names": [ "Lung Adenocarcinoma", "Lung Adenocarcinoma", "Lung Cancer" ] } ], "allele_id": 27405, "clinical_significance": [ "Pathogenic" ], "submissions": [ { "submitter_name": "Liquid Biopsy and Cancer Interception Group, Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research", "submission_description": [], "submitter_date": 20230220, "review_description": "Pathogenic", "review_status": "criteria provided, single submitter", "review_date": 20220606, "origin": "somatic", "method": "research", "date_updated": 20230304, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "symbols": { "mondo": "MONDO:0005061" } } ], "accession_id": "SCV003806294" }, { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "submitter_date": 20160718, "review_description": "Likely pathogenic", "review_status": "no assertion criteria provided", "review_date": 20160531, "origin": "somatic", "method": "literature only", "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "diseases": [ { "symbols": { "mesh": "C538231" } } ], "accession_id": "SCV000504683" } ], "date_created": 20170308, "review_date": 20220606, "review_status": "criteria provided, single submitter", "review_description": "Pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Lung adenocarcinoma", "review_stars": 1, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV002476955", "diseases": [ { "normalized_disease": [ "Adrenocortical Carcinoma, Hereditary" ], "symbols": { "orphanet": "1501", "omim": "202300", "medgen": "C1859972", "mondo": "MONDO:0008734" }, "normalized_cancer": [ "Adrenocortical Carcinoma" ], "names": [ "Adrenocortical Carcinoma, Hereditary" ], "keyword": "Hereditary cancer syndrome" }, { "pub_med": [ 15604628, 18163131, 17508274, 24366376, 24366402, 24432435, 26389210, 26389258, 34242744, 31429903 ], "normalized_disease": [ "Hereditary Breast Carcinoma" ], "symbols": { "omim": "114480", "medgen": "C0346153", "mondo": "MONDO:0016419" }, "normalized_cancer": [ "Breast" ], "names": [ "Hereditary Breast Carcinoma", "Hereditary Breast Carcinoma" ], "keyword": "Hereditary cancer syndrome", "disease_mechanism": "loss of function" }, { "normalized_disease": [ "Glioma Susceptibility 1" ], "symbols": { "omim": "137800", "medgen": "C2750850", "mondo": "MONDO:0024498" }, "normalized_cancer": [ "Glioma susceptibility 1", "Glioblastoma, somatic" ], "names": [ "Glioma Susceptibility 1", "Glioma Susceptibility 1" ], "keyword": "Neoplasm" }, { "normalized_disease": [ "Bone Osteosarcoma" ], "symbols": { "orphanet": "668", "omim": "259500", "medgen": "C0585442", "mondo": "MONDO:0002629" }, "normalized_cancer": [ "Osteosarcoma, somatic" ], "names": [ "Bone Osteosarcoma", "Bone Osteosarcoma" ] }, { "pub_med": [ 17392385, 20065170, 12692171, 15604628, 23788249, 24493721, 25394175, 25356965, 26389258, 26324357 ], "normalized_disease": [ "Li-Fraumeni Syndrome" ], "symbols": { "orphanet": "524", "omim": "151623", "medgen": "C1835398", "gene": "553989" }, "names": [ "Li-Fraumeni Syndrome" ] }, { "normalized_disease": [ "Malignant Tumor of Nasopharynx", "Nasopharyngeal Carcinoma, Susceptibility to, 1" ], "symbols": { "orphanet": "150", "omim": "607107", "medgen": "C2931822", "mondo": "MONDO:0015459" }, "normalized_cancer": [ "Nasopharyngeal Carcinoma" ], "names": [ "Malignant Tumor of Nasopharynx", "Nasopharyngeal Carcinoma, Susceptibility to, 1" ], "keyword": "Hereditary cancer syndrome" }, { "pub_med": [ 17060676, 24493721, 25394175 ], "normalized_disease": [ "Exocrine Pancreatic Carcinoma", "Familial Pancreatic Carcinoma" ], "symbols": { "orphanet": "1333", "omim": "260350", "medgen": "C0235974", "mesh": "C562463", "mondo": "MONDO:0005192" }, "normalized_cancer": [ "Pancreas" ], "names": [ "Exocrine Pancreatic Carcinoma", "Pancreatic Acinar Carcinoma", "Exocrine Pancreatic Carcinoma", "Familial Pancreatic Carcinoma", "Familial Pancreatic Carcinoma", "Exocrine Pancreatic Carcinoma" ], "disease_mechanism": "loss of function" }, { "normalized_disease": [ "Choroid Plexus Papilloma" ], "symbols": { "orphanet": "251899", "omim": "260500", "medgen": "C0205770", "mondo": "MONDO:0009837", "human_phenotype_ontology": "HP:0200022" }, "normalized_cancer": [ "Choroid Plexus Papilloma" ], "names": [ "Choroid Plexus Papilloma", "Choroid Plexus Papilloma" ] }, { "normalized_disease": [ "Basal Cell Carcinoma, Susceptibility to, 7" ], "symbols": { "omim": "614740", "medgen": "C3553606", "mondo": "MONDO:0013876" }, "normalized_cancer": [ "Basal Cell Carcinoma" ], "names": [ "Basal Cell Carcinoma, Susceptibility to, 7" ] }, { "normalized_disease": [ "Carcinoma of Liver and Intrahepatic Biliary Tract", "Hepatocellular Carcinoma", "Adult Hepatocellular Carcinoma" ], "symbols": { "omim": "114550", "medgen": "C2239176", "mondo": "MONDO:0007256", "human_phenotype_ontology": "HP:0006750" }, "normalized_cancer": [ "Hepatocellular Carcinoma", "Liver", "Hepatocellular cancer" ], "names": [ "Carcinoma of Liver and Intrahepatic Biliary Tract", "Primary Carcinoma Liver", "Hepatocellular Carcinoma", "Hepatocellular Carcinoma", "Adult Hepatocellular Carcinoma" ], "keyword": "Hereditary cancer syndrome" }, { "pub_med": [ 26389505, 26389258, 34043773 ], "normalized_disease": [ "Colorectal Cancer" ], "symbols": { "omim": "114500", "medgen": "C0346629", "mondo": "MONDO:0005575" }, "normalized_cancer": [ "Colorectal cancer", "Colorectal cancer, somatic", "Malignant Colorectal Neoplasm" ], "names": [ "Colorectal Cancer", "Colorectal Cancer", "Colorectal Cancer" ] }, { "normalized_disease": [ "Bone Marrow Failure Syndrome 5" ], "symbols": { "omim": "618165", "medgen": "C4748488", "mondo": "MONDO:0032573" }, "names": [ "Bone Marrow Failure Syndrome 5" ] } ], "allele_id": 27405, "clinical_significance": [ "Pathogenic" ], "submissions": [ { "submitter_name": "Fulgent Genetics, Fulgent Genetics", "submission_description": [], "submitter_date": 20221213, "review_description": "Pathogenic", "review_status": "criteria provided, single submitter", "review_date": 20220314, "origin": "unknown", "method": "clinical testing", "date_updated": 20221231, "clinical_significance": [ "Pathogenic" ], "accession_id": "SCV000611327" } ], "date_created": 20221231, "review_date": 20220314, "review_status": "criteria provided, single submitter", "review_description": "Pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND multiple conditions", "review_stars": 1, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV000115738", "diseases": [ { "pub_med": [ 25394175 ], "normalized_disease": [ "Hereditary Neoplastic Syndrome" ], "symbols": { "medgen": "C0027672", "mesh": "D009386", "mondo": "MONDO:0015356" }, "normalized_cancer": [ "Tumor predisposition", "Cancer predisposition", "Hereditary Cancer Syndrome" ], "names": [ "Hereditary Cancer-Predisposing Syndrome", "Hereditary Neoplastic Syndrome", "Tumor Predisposition", "Cancer Predisposition", "Hereditary Neoplastic Syndrome", "Hereditary Neoplastic Syndrome" ], "keyword": "Hereditary cancer syndrome" } ], "allele_id": 27405, "clinical_significance": [ "Pathogenic", "Likely pathogenic" ], "submissions": [ { "submitter_name": "Ambry Genetics", "submission_description": [ "The p.R273H pathogenic mutation (also known as c.818G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 818. The arginine at codon 273 is replaced by histidine, an amino acid with highly similar properties. This alteration occurs at a well-characterized mutation \"hotspot\" located within the functionally critical DNA binding domain, and is associated with a classic LFS-associated tumor spectrum, including soft tissue and osteosarcomas, breast cancer, and central nervous system malignancies (Petitjean A et al. IARC TP53 database [version R16, November 2012]. Hum. Mutat. 2007 Jun;28(6):622-9). To date, the p.R273H mutation has been detected in numerous individuals/families satisfying classic criteria for LFS and has segregated with disease in all families with multiple informative relatives tested (Ambry internal data). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation." ], "submitter_date": 20221111, "review_description": "Pathogenic", "review_status": "criteria provided, single submitter", "review_date": 20210824, "origin": "germline", "method": "clinical testing", "date_updated": 20221129, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "symbols": { "medgen": "C0027672" } } ], "accession_id": "SCV000186052" }, { "submitter_name": "Color Diagnostics, LLC DBA Color Health", "submission_description": [ "This missense variant replaces arginine with histidine at codon 273 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown the mutant protein to be non-functional in transactivation assays (IARC database, PMID: 12826609, 20407015, 25584008) and cell growth assays (PMID: 24677579, 25584008, 29979965, 30224644). This variant has been reported in individuals affected with classic Li-Fraumeni syndrome (PMID: 1565144, 7732013, 10864200, 15390294, 16401470, 27374712) and in individuals meeting the Chompret criteria for Li-Fraumeni syndrome (PMID: 9242456, 25584008, 25787918). This variant has been identified in 4/251054 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic." ], "submitter_date": 20210611, "review_description": "Pathogenic", "review_status": "criteria provided, single submitter", "review_date": 20210112, "origin": "germline", "method": "clinical testing", "date_updated": 20210619, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "symbols": { "medgen": "C0027672" } } ], "accession_id": "SCV001735236" }, { "submitter_name": "GeneKor MSA", "submission_description": [ "This sequence change replaces Arginine with Histidine at codon 273 of the TP53 protein. The arginine residue is highly conserved among species and is located in a functional domain of the protein which interacts with multiple proteins. There is a large physiochemical difference between arginine and histidine (Grantham Score 29). There is a large physiochemical difference between arginine and tryptophan (Grantham Score 101).This variant is present in population databases at a very low frequency ( rs28934576, ExAC 0.02%) and has been reported in multiple individuals and families affected with Li-Fraumeni and Li-Fraumeni-like syndromes (PMID: 17540308, 1565144, 20693561). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging to the protein. In addition, experimental studies have shown that this variant affects TP53 transactivation activity at variable levels(PMID: 12826609). In summary, this is a rare sequence change that is expected to affect the TP53 protein and cause disease.The mutation database Clinvar contains entries for this variant (Variation ID: 12366)" ], "submitter_date": 20200306, "review_description": "Likely pathogenic", "review_status": "criteria provided, single submitter", "review_date": 20200101, "origin": "germline", "method": "clinical testing", "date_updated": 20200504, "clinical_significance": [ "Likely pathogenic" ], "diseases": [ { "symbols": { "medgen": "C0027672" }, "names": [ "Hereditary Cancer-Predisposing Syndrome" ] } ], "accession_id": "SCV000821786" } ], "date_created": 20140517, "review_date": 20210824, "review_status": "criteria provided, multiple submitters, no conflicts", "review_description": "Pathogenic/Likely pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Hereditary cancer-predisposing syndrome", "review_stars": 2, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV003162246", "diseases": [ { "normalized_disease": [ "Gastric Cancer" ], "symbols": { "omim": "613659", "medgen": "C0024623", "mesh": "D013274", "mondo": "MONDO:0001056", "human_phenotype_ontology": "HP:0012126" }, "normalized_cancer": [ "Esophagus/Stomach", "Malignant Tumor" ], "names": [ "Gastric Cancer", "Gastric Cancer", "Gastric Cancer" ] } ], "allele_id": 27405, "clinical_significance": [ "Pathogenic" ], "submissions": [ { "submitter_name": "Laboratory for Genotyping Development, RIKEN", "submission_description": [], "submitter_date": 20221201, "review_description": "Pathogenic", "review_status": "no assertion criteria provided", "review_date": 20210701, "origin": "germline", "method": "research", "date_updated": 20230415, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "symbols": { "mesh": "D013274" } } ], "accession_id": "SCV002758479" } ], "date_created": 20230415, "review_date": 20210701, "review_status": "no assertion criteria provided", "review_description": "Pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Gastric cancer", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV001527484", "diseases": [ { "pub_med": [ 15604628, 18163131, 17508274, 24366376, 24366402, 24432435, 26389210, 26389258, 34242744, 31429903 ], "normalized_disease": [ "Hereditary Breast Carcinoma" ], "symbols": { "omim": "114480", "medgen": "C0346153", "mondo": "MONDO:0016419" }, "normalized_cancer": [ "Breast" ], "names": [ "Hereditary Breast Carcinoma", "Hereditary Breast Carcinoma" ], "keyword": "Hereditary cancer syndrome", "disease_mechanism": "loss of function" } ], "allele_id": 27405, "clinical_significance": [ "Pathogenic" ], "submissions": [ { "submitter_name": "University Health Network, Princess Margaret Cancer Centre", "submission_description": [], "submitter_date": 20210519, "review_description": "Pathogenic", "review_status": "no assertion criteria provided", "review_date": 20210319, "origin": "somatic", "method": "clinical testing", "date_updated": 20210626, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "symbols": { "omim": "114480" } } ], "accession_id": "SCV001738505" } ], "date_created": 20210626, "review_date": 20210319, "review_status": "no assertion criteria provided", "review_description": "Pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Familial cancer of breast", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV001527470", "diseases": [ { "normalized_disease": [ "Plasma Cell Myeloma", "Plasma Cell Neoplasm" ], "symbols": { "orphanet": "85443", "omim": "254500", "medgen": "C0026764", "mesh": "D009101", "mondo": "MONDO:0009693", "human_phenotype_ontology": "HP:0006775" }, "normalized_cancer": [ "Plasma Cell Myeloma" ], "names": [ "Plasma Cell Myeloma", "Plasma Cell Myeloma", "Plasma Cell Myeloma", "Plasma Cell Myeloma", "Plasma Cell Neoplasm", "Multiple Myeloma, Somatic" ], "keyword": "Hereditary cancer syndrome" }, { "pub_med": [ 26389505, 26389258, 34043773 ], "normalized_disease": [ "Colorectal Cancer" ], "symbols": { "omim": "114500", "medgen": "C0346629", "mondo": "MONDO:0005575" }, "normalized_cancer": [ "Colorectal cancer", "Colorectal cancer, somatic", "Malignant Colorectal Neoplasm" ], "names": [ "Colorectal Cancer", "Colorectal Cancer", "Colorectal Cancer" ] } ], "allele_id": 27405, "clinical_significance": [ "Pathogenic" ], "submissions": [ { "submitter_name": "University Health Network, Princess Margaret Cancer Centre", "submission_description": [], "submitter_date": 20210519, "review_description": "Pathogenic", "review_status": "no assertion criteria provided", "review_date": 20210319, "origin": "somatic", "method": "clinical testing", "date_updated": 20210626, "clinical_significance": [ "Pathogenic" ], "accession_id": "SCV001738487" } ], "date_created": 20210626, "review_date": 20210319, "review_status": "no assertion criteria provided", "review_description": "Pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND multiple conditions", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV000785345", "diseases": [ { "pub_med": [ 19042984, 22964825, 23188549, 33410258, 29450531 ], "normalized_disease": [ "Ovarian Neoplasm", "Ovarian Cancer" ], "symbols": { "omim": "167000", "medgen": "C0919267", "mesh": "D010051", "mondo": "MONDO:0021068", "human_phenotype_ontology": "HP:0100615" }, "normalized_cancer": [ "Ovary/Fallopian Tube", "Ovarian Cancer, Other" ], "names": [ "Ovarian Neoplasm", "Ovarian Neoplasm", "Ovarian Cancer", "Ovarian Neoplasm", "Ovarian Neoplasms" ] } ], "allele_id": 27405, "clinical_significance": [ "Pathogenic", "Likely pathogenic" ], "submissions": [ { "submitter_name": "University Health Network, Princess Margaret Cancer Centre", "submission_description": [], "submitter_date": 20210519, "review_description": "Pathogenic", "review_status": "no assertion criteria provided", "review_date": 20210319, "origin": "somatic", "method": "clinical testing", "date_updated": 20210626, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "symbols": { "omim": "167000" } } ], "accession_id": "SCV001738490" }, { "submitter_name": "German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne", "submission_description": [], "submitter_date": 20190222, "review_description": "Likely pathogenic", "review_status": "no assertion criteria provided", "review_date": 20181201, "date_updated": 20190617, "clinical_significance": [ "Likely pathogenic" ], "diseases": [ { "symbols": { "mesh": "D010051" } } ], "accession_id": "SCV000923913" } ], "date_created": 20190617, "review_date": 20210319, "review_status": "no assertion criteria provided", "review_description": "Pathogenic/Likely pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Neoplasm of ovary", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV001257517", "diseases": [ { "normalized_disease": [ "Rhabdomyosarcoma" ], "symbols": { "medgen": "C0035412", "mesh": "D012208", "mondo": "MONDO:0005212", "human_phenotype_ontology": "HP:0002859" }, "names": [ "Rhabdomyosarcoma", "Rhabdomyosarcoma" ] } ], "allele_id": 27405, "clinical_significance": [ "Pathogenic" ], "submissions": [ { "submitter_name": "Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine", "submission_description": [], "submitter_date": 20200906, "review_description": "Pathogenic", "review_status": "no assertion criteria provided", "review_date": 20200901, "origin": "germline", "method": "provider interpretation", "date_updated": 20201003, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "normalized_disease": [ "Rhabdomyosarcoma" ], "names": [ "Rhabdomyosarcoma" ] } ], "accession_id": "SCV001434343" } ], "date_created": 20201003, "review_date": 20200901, "review_status": "no assertion criteria provided", "review_description": "Pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Rhabdomyosarcoma", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV000463420", "diseases": [ { "pub_med": [ 17392385, 24493721, 26389210, 26389258 ], "normalized_disease": [ "Li-Fraumeni Syndrome" ], "symbols": { "omim": "151623", "medgen": "C0085390", "mondo": "MONDO:0018875" }, "normalized_cancer": [ "Sarcoma family syndrome of Li and Fraumeni" ], "names": [ "Li-Fraumeni Syndrome", "Sarcoma Family Syndrome Li Fraumeni" ] } ], "allele_id": 27405, "clinical_significance": [ "Pathogenic" ], "submissions": [ { "submitter_name": "Invitae", "submission_description": [ "This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 273 of the TP53 protein (p.Arg273His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (LFS) (PMID: 1565144, 9242456, 17540308, 20693561, 21484931, 21552135). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12366). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic." ], "submitter_date": 20230106, "review_description": "Pathogenic", "review_status": "criteria provided, single submitter", "review_date": 20221025, "origin": "germline", "method": "clinical testing", "date_updated": 20230207, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "symbols": { "medgen": "C0085390" } } ], "accession_id": "SCV000545317" }, { "submitter_name": "ClinGen TP53 Variant Curation Expert Panel, ClinGen", "submission_description": [ "This variant is within a codon that is an established hotspot in the TP53 gene (PM1; PMID: 2046748). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 15 or higher (PP3). Transactivation assays show a low functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3; PMID: 12826609, 30224644). This variant has been reported in at least 2 probands meeting classic Li-Fraumeni syndrome criteria and 4 probands meeting Chompret criteria (PS4; PMID: 16401470, 15390294, 9242456, 10864200, 1565144, 7732013). Additionally, there is a de novo observation of a proband with breast cancer at age 29 with parental confirmation (PS2; PMID: 12672316). In summary, TP53 c.818G>A; p.Arg273His meets criteria to be classified as pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM1, PP3, PS3, PS4, PS2." ], "submitter_date": 20190923, "review_description": "Pathogenic", "review_status": "reviewed by expert panel", "review_date": 20190828, "origin": "germline", "method": "curation", "date_updated": 20200112, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "symbols": { "orphanet": "ORPHA524" } } ], "accession_id": "SCV001142550" }, { "submitter_name": "Mendelics", "submission_description": [], "submitter_date": 20180820, "review_description": "Pathogenic", "review_status": "criteria provided, single submitter", "review_date": 20180702, "origin": "unknown", "method": "clinical testing", "date_updated": 20221211, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "normalized_disease": [ "Li-Fraumeni Syndrome" ], "symbols": { "medgen": "C0085390" }, "names": [ "Li-Fraumeni Syndrome" ] } ], "accession_id": "SCV000839110" }, { "submitter_name": "Women's Health and Genetics/Laboratory Corporation of America, LabCorp", "submission_description": [ "Variant summary: The TP53 c.818G>A (p.Arg273His) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/114148 control chromosomes at a frequency of 0.0000263, which does not exceed the estimated maximal expected allele frequency of a pathogenic TP53 variant (0.0000398). The variant has been reported in numerous affected individuals in the literature and the codon location is a known hotspot mutation occurring as a frequent mutation in affected individuals. Functional studies report a dominant negative affect of the variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic." ], "submitter_date": 20180125, "review_description": "Pathogenic", "review_status": "criteria provided, single submitter", "review_date": 20170209, "origin": "germline", "method": "clinical testing", "date_updated": 20171226, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "symbols": { "medgen": "C0085390" } } ], "accession_id": "SCV000697450" } ], "date_created": 20170417, "review_date": 20190828, "review_status": "reviewed by expert panel", "review_description": "Pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Li-Fraumeni syndrome", "review_stars": 3, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV000435547", "diseases": [ { "normalized_disease": [ "Carcinoma of Esophagus" ], "symbols": { "orphanet": "70482", "medgen": "C0152018", "mondo": "MONDO:0019086", "human_phenotype_ontology": "HP:0011459" }, "normalized_cancer": [ "Esophagus/Stomach", "Oesophageal carcinoma" ], "names": [ "Carcinoma of Esophagus", "Oesophageal Carcinoma", "Carcinoma of Esophagus" ] } ], "allele_id": 27405, "clinical_significance": [ "Likely pathogenic" ], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "submitter_date": 20160718, "review_description": "Likely pathogenic", "review_status": "no assertion criteria provided", "review_date": 20160531, "origin": "somatic", "method": "literature only", "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "diseases": [ { "symbols": { "medgen": "C0152018" } } ], "accession_id": "SCV000504672" } ], "date_created": 20170308, "review_date": 20160531, "review_status": "no assertion criteria provided", "review_description": "Likely pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Carcinoma of esophagus", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV000437210", "diseases": [ { "normalized_disease": [ "Small Cell Lung Carcinoma" ], "symbols": { "orphanet": "70573", "omim": "182280", "medgen": "C0149925", "mesh": "D055752", "mondo": "MONDO:0008433", "human_phenotype_ontology": "HP:0030357" }, "normalized_cancer": [ "Small Cell Lung Cancer", "Lung" ], "names": [ "Small Cell Lung Carcinoma", "Small Cell Lung Carcinoma", "Small Cell Lung Carcinoma", "Small Cell Lung Carcinoma" ] } ], "allele_id": 27405, "clinical_significance": [ "Likely pathogenic" ], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "submitter_date": 20160718, "review_description": "Likely pathogenic", "review_status": "no assertion criteria provided", "review_date": 20160531, "origin": "somatic", "method": "literature only", "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "diseases": [ { "symbols": { "mesh": "D055752" } } ], "accession_id": "SCV000504678" } ], "date_created": 20170308, "review_date": 20160531, "review_status": "no assertion criteria provided", "review_description": "Likely pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Small cell lung carcinoma", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV000439513", "diseases": [ { "normalized_disease": [ "Pancreatic Adenocarcinoma" ], "symbols": { "medgen": "C0281361", "mondo": "MONDO:0006047", "human_phenotype_ontology": "HP:0006725" }, "normalized_cancer": [ "Pancreatic Adenocarcinoma" ], "names": [ "Pancreatic Adenocarcinoma" ] } ], "allele_id": 27405, "clinical_significance": [ "Likely pathogenic" ], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "submitter_date": 20160718, "review_description": "Likely pathogenic", "review_status": "no assertion criteria provided", "review_date": 20160531, "origin": "somatic", "method": "literature only", "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "diseases": [ { "symbols": { "medgen": "C0281361" } } ], "accession_id": "SCV000504661" } ], "date_created": 20170308, "review_date": 20160531, "review_status": "no assertion criteria provided", "review_description": "Likely pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Pancreatic adenocarcinoma", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV000440474", "diseases": [ { "normalized_disease": [ "Medulloblastoma" ], "symbols": { "orphanet": "616", "omim": "155255", "medgen": "C0025149", "mesh": "D008527", "mondo": "MONDO:0007959", "human_phenotype_ontology": "HP:0002885" }, "normalized_cancer": [ "Medulloblastoma, somatic" ], "names": [ "Medulloblastoma", "Medulloblastoma", "Medulloblastoma Predisposition Syndrome" ], "keyword": "Hereditary cancer syndrome" } ], "allele_id": 27405, "clinical_significance": [ "Likely pathogenic" ], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "submitter_date": 20160718, "review_description": "Likely pathogenic", "review_status": "no assertion criteria provided", "review_date": 20160531, "origin": "somatic", "method": "literature only", "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "diseases": [ { "symbols": { "mesh": "D008527" } } ], "accession_id": "SCV000504681" } ], "date_created": 20170308, "review_date": 20160531, "review_status": "no assertion criteria provided", "review_description": "Likely pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Medulloblastoma", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV000440815", "diseases": [ { "pub_med": [ 22138009, 23970018, 32171751 ], "normalized_disease": [ "Acute Myeloid Leukemia" ], "symbols": { "orphanet": "519", "omim": "601626", "medgen": "C0023467", "mesh": "D015470", "mondo": "MONDO:0018874", "human_phenotype_ontology": "HP:0006728" }, "normalized_cancer": [ "Acute Myeloid Leukemia", "Acute myelogenous leukemia", "Acute non-lymphocytic leukemia", "Acute granulocytic leukemia", "Leukemia, acute myelogenous, somatic" ], "names": [ "Acute Myeloid Leukemia", "Acute Myeloid Leukemia, Adult", "Aml Adult", "Acute Myeloid Leukemia", "Acute Myeloid Leukemia", "Acute Myeloid Leukemia", "Acute Myeloid Leukemia", "Leukemia, Acute Myelogenous, Somatic" ], "disease_mechanism": "Constitutively activated FLT3" } ], "allele_id": 27405, "clinical_significance": [ "Likely pathogenic" ], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "submitter_date": 20160718, "review_description": "Likely pathogenic", "review_status": "no assertion criteria provided", "review_date": 20160531, "origin": "somatic", "method": "literature only", "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "diseases": [ { "symbols": { "mesh": "D015470" } } ], "accession_id": "SCV000504664" } ], "date_created": 20170308, "review_date": 20160531, "review_status": "no assertion criteria provided", "review_description": "Likely pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Acute myeloid leukemia", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV000443907", "diseases": [ { "pub_med": [ 17954709, 23917950, 23970019, 24088296, 19042984, 22138009, 23188549, 24799465, 24799487, 25488926, 23835710, 24061412, 27557300, 33410258, 29939838, 29939840, 31479144, 34242744 ], "normalized_disease": [ "Breast Neoplasm" ], "symbols": { "medgen": "C1458155", "mesh": "D001943", "mondo": "MONDO:0021100", "human_phenotype_ontology": "HP:0010623" }, "normalized_cancer": [ "Breast Neoplasm, NOS", "Breast" ], "names": [ "Breast Neoplasm", "Breast Neoplasm", "Breast Neoplasm", "Breast Neoplasm", "Breast Neoplasms" ], "disease_mechanism": "gain of function" } ], "allele_id": 27405, "clinical_significance": [ "Likely pathogenic" ], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "submitter_date": 20160718, "review_description": "Likely pathogenic", "review_status": "no assertion criteria provided", "review_date": 20160531, "origin": "somatic", "method": "literature only", "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "diseases": [ { "symbols": { "mesh": "D001943" } } ], "accession_id": "SCV000504673" } ], "date_created": 20170308, "review_date": 20160531, "review_status": "no assertion criteria provided", "review_description": "Likely pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Breast neoplasm", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV000444851", "diseases": [ { "normalized_disease": [ "Carcinoma of Liver and Intrahepatic Biliary Tract", "Hepatocellular Carcinoma", "Adult Hepatocellular Carcinoma" ], "symbols": { "omim": "114550", "medgen": "C2239176", "mondo": "MONDO:0007256", "human_phenotype_ontology": "HP:0006750" }, "normalized_cancer": [ "Hepatocellular Carcinoma", "Liver", "Hepatocellular cancer" ], "names": [ "Carcinoma of Liver and Intrahepatic Biliary Tract", "Primary Carcinoma Liver", "Hepatocellular Carcinoma", "Hepatocellular Carcinoma", "Adult Hepatocellular Carcinoma" ], "keyword": "Hereditary cancer syndrome" } ], "allele_id": 27405, "clinical_significance": [ "Likely pathogenic" ], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "submitter_date": 20160718, "review_description": "Likely pathogenic", "review_status": "no assertion criteria provided", "review_date": 20160531, "origin": "somatic", "method": "literature only", "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "diseases": [ { "symbols": { "omim": "114550" } } ], "accession_id": "SCV000504667" } ], "date_created": 20170308, "review_date": 20160531, "review_status": "no assertion criteria provided", "review_description": "Likely pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Hepatocellular carcinoma", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV000444900", "diseases": [ { "pub_med": [ 23012255 ], "normalized_disease": [ "Colorectal Neoplasm" ], "symbols": { "medgen": "C0009404", "mesh": "D015179", "mondo": "MONDO:0005335", "human_phenotype_ontology": "HP:0100834" }, "normalized_cancer": [ "Neoplasm of the large intestine", "Colorectal Neoplasms", "Colorectal neoplasm" ], "names": [ "Neoplasm Large Intestine", "Colorectal Neoplasms", "Colorectal Neoplasm" ] } ], "allele_id": 27405, "clinical_significance": [ "Likely pathogenic" ], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "submitter_date": 20160718, "review_description": "Likely pathogenic", "review_status": "no assertion criteria provided", "review_date": 20160531, "origin": "somatic", "method": "literature only", "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "diseases": [ { "symbols": { "mesh": "D015179" } } ], "accession_id": "SCV000504670" } ], "date_created": 20170308, "review_date": 20160531, "review_status": "no assertion criteria provided", "review_description": "Likely pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Neoplasm of the large intestine", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV000434044", "allele_id": 27405, "clinical_significance": [ "Likely pathogenic" ], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "submitter_date": 20160718, "review_description": "Likely pathogenic", "review_status": "no assertion criteria provided", "review_date": 20160531, "origin": "somatic", "method": "literature only", "finding": [ { "symbols": { "medgen": "C0677865" } } ], "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "accession_id": "SCV000504669" } ], "date_created": 20170308, "finding": [ { "normalized_phenotype": [ "Brainstem Glioma" ], "symbols": { "medgen": "C0677865", "mondo": "MONDO:0002911", "human_phenotype_ontology": "HP:0010796" }, "names": [ "Childhood Brain Stem Glioma" ] } ], "review_date": 20160531, "review_status": "no assertion criteria provided", "review_description": "Likely pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Brainstem glioma", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV000418930", "diseases": [ { "normalized_disease": [ "Squamous Cell Lung Carcinoma" ], "symbols": { "medgen": "C0149782", "mondo": "MONDO:0005097", "human_phenotype_ontology": "HP:0030359" }, "normalized_cancer": [ "Lung Squamous Cell Carcinoma", "Lung" ], "names": [ "Squamous Cell Lung Carcinoma", "Lung Cancer, Squamous Cell, Somatic", "Squamous Cell Lung Carcinoma" ], "keyword": "Neoplasm" } ], "allele_id": 27405, "clinical_significance": [ "Likely pathogenic" ], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "submitter_date": 20160718, "review_description": "Likely pathogenic", "review_status": "no assertion criteria provided", "review_date": 20160531, "origin": "somatic", "method": "literature only", "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "diseases": [ { "symbols": { "medgen": "C0149782" } } ], "accession_id": "SCV000504676" } ], "date_created": 20170308, "review_date": 20160531, "review_status": "no assertion criteria provided", "review_description": "Likely pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Squamous cell lung carcinoma", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV000419960", "diseases": [ { "normalized_disease": [ "Gastric Adenocarcinoma" ], "symbols": { "medgen": "C0278701", "mondo": "MONDO:0005036", "human_phenotype_ontology": "HP:0033770" }, "normalized_cancer": [ "Esophagus/Stomach", "Stomach Adenocarcinoma" ], "names": [ "Gastric Adenocarcinoma", "Gastric Adenocarcinoma" ] } ], "allele_id": 27405, "clinical_significance": [ "Likely pathogenic" ], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "submitter_date": 20160718, "review_description": "Likely pathogenic", "review_status": "no assertion criteria provided", "review_date": 20160531, "origin": "somatic", "method": "literature only", "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "diseases": [ { "symbols": { "medgen": "C0278701" } } ], "accession_id": "SCV000504679" } ], "date_created": 20170308, "review_date": 20160531, "review_status": "no assertion criteria provided", "review_description": "Likely pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Gastric adenocarcinoma", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV000422733", "diseases": [ { "normalized_disease": [ "Prostate Adenocarcinoma" ], "symbols": { "medgen": "C0007112", "mondo": "MONDO:0005082" }, "normalized_cancer": [ "Prostate Adenocarcinoma" ], "names": [ "Prostate Adenocarcinoma", "Prostate Adenocarcinoma" ] } ], "allele_id": 27405, "clinical_significance": [ "Likely pathogenic" ], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "submitter_date": 20160718, "review_description": "Likely pathogenic", "review_status": "no assertion criteria provided", "review_date": 20160531, "origin": "somatic", "method": "literature only", "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "diseases": [ { "symbols": { "medgen": "C0007112" } } ], "accession_id": "SCV000504665" } ], "date_created": 20170308, "review_date": 20160531, "review_status": "no assertion criteria provided", "review_description": "Likely pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Prostate adenocarcinoma", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV000423826", "diseases": [ { "normalized_disease": [ "Carcinosarcoma of the Corpus Uteri" ], "symbols": { "medgen": "C0280630", "mondo": "MONDO:0006485" }, "normalized_cancer": [ "Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian Tumor" ], "names": [ "Carcinosarcoma of the Corpus Uteri" ] } ], "allele_id": 27405, "clinical_significance": [ "Likely pathogenic" ], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "submitter_date": 20160718, "review_description": "Likely pathogenic", "review_status": "no assertion criteria provided", "review_date": 20160531, "origin": "somatic", "method": "literature only", "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "diseases": [ { "symbols": { "medgen": "C0280630" } } ], "accession_id": "SCV000504685" } ], "date_created": 20170308, "review_date": 20160531, "review_status": "no assertion criteria provided", "review_description": "Likely pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Uterine carcinosarcoma", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV000424109", "diseases": [ { "normalized_disease": [ "B-Cell Chronic Lymphocytic Leukemia" ], "symbols": { "orphanet": "67038", "omim": "151400", "medgen": "C0023434", "mesh": "D015451", "mondo": "MONDO:0004948", "human_phenotype_ontology": "HP:0006760" }, "normalized_cancer": [ "Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma", "Mature B-Cell Neoplasms", "Chronic lymphatic leukemia" ], "names": [ "B-Cell Chronic Lymphocytic Leukemia", "B-Cell Chronic Lymphocytic Leukemia", "Leukemia, B-Cell, Chronic", "B-Cell Chronic Lymphocytic Leukemia" ] } ], "allele_id": 27405, "clinical_significance": [ "Likely pathogenic" ], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "submitter_date": 20160718, "review_description": "Likely pathogenic", "review_status": "no assertion criteria provided", "review_date": 20160531, "origin": "somatic", "method": "literature only", "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "diseases": [ { "symbols": { "mesh": "D015451" } } ], "accession_id": "SCV000504682" } ], "date_created": 20170308, "review_date": 20160531, "review_status": "no assertion criteria provided", "review_description": "Likely pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND B-cell chronic lymphocytic leukemia", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV000424218", "diseases": [ { "normalized_disease": [ "Brain Neoplasm" ], "symbols": { "medgen": "C0006118", "mesh": "D001932", "mondo": "MONDO:0021211", "human_phenotype_ontology": "HP:0030692" }, "normalized_cancer": [ "CNS/Brain" ], "names": [ "Brain Neoplasm", "Brain Neoplasm", "Brain Neoplasm", "Brain Neoplasm" ] } ], "allele_id": 27405, "clinical_significance": [ "Likely pathogenic" ], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "submitter_date": 20160718, "review_description": "Likely pathogenic", "review_status": "no assertion criteria provided", "review_date": 20160531, "origin": "somatic", "method": "literature only", "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "diseases": [ { "symbols": { "mesh": "D001932" } } ], "accession_id": "SCV000504668" } ], "date_created": 20170308, "review_date": 20160531, "review_status": "no assertion criteria provided", "review_description": "Likely pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Neoplasm of brain", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV000424627", "diseases": [ { "normalized_disease": [ "Malignant Tumor of Adrenal Cortex", "Adrenal Cortex Carcinoma" ], "symbols": { "medgen": "C0206686", "mesh": "D018268", "mondo": "MONDO:0006639", "human_phenotype_ontology": "HP:0006759" }, "normalized_cancer": [ "Adrenal cortex carcinoma", "Adrenocortical Carcinoma" ], "names": [ "Malignant Tumor of Adrenal Cortex", "Adrenal Cortex Carcinoma" ] } ], "allele_id": 27405, "clinical_significance": [ "Likely pathogenic" ], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "submitter_date": 20160718, "review_description": "Likely pathogenic", "review_status": "no assertion criteria provided", "review_date": 20160531, "origin": "somatic", "method": "literature only", "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "diseases": [ { "symbols": { "mesh": "D018268" } } ], "accession_id": "SCV000504674" } ], "date_created": 20170308, "review_date": 20160531, "review_status": "no assertion criteria provided", "review_description": "Likely pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Adrenal cortex carcinoma", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV000424833", "diseases": [ { "normalized_disease": [ "Plasma Cell Myeloma", "Plasma Cell Neoplasm" ], "symbols": { "orphanet": "85443", "omim": "254500", "medgen": "C0026764", "mesh": "D009101", "mondo": "MONDO:0009693", "human_phenotype_ontology": "HP:0006775" }, "normalized_cancer": [ "Plasma Cell Myeloma" ], "names": [ "Plasma Cell Myeloma", "Plasma Cell Myeloma", "Plasma Cell Myeloma", "Plasma Cell Myeloma", "Plasma Cell Neoplasm", "Multiple Myeloma, Somatic" ], "keyword": "Hereditary cancer syndrome" } ], "allele_id": 27405, "clinical_significance": [ "Likely pathogenic" ], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "submitter_date": 20160718, "review_description": "Likely pathogenic", "review_status": "no assertion criteria provided", "review_date": 20160531, "origin": "somatic", "method": "literature only", "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "diseases": [ { "symbols": { "mesh": "D009101" } } ], "accession_id": "SCV000504671" } ], "date_created": 20170308, "review_date": 20160531, "review_status": "no assertion criteria provided", "review_description": "Likely pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Multiple myeloma", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV000428779", "diseases": [ { "normalized_disease": [ "Ovarian Serous Cystadenocarcinoma" ], "symbols": { "medgen": "C0279663", "mondo": "MONDO:0006046" }, "normalized_cancer": [ "Serous Ovarian Cancer" ], "names": [ "Ovarian Serous Cystadenocarcinoma" ] } ], "allele_id": 27405, "clinical_significance": [ "Likely pathogenic" ], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "submitter_date": 20160718, "review_description": "Likely pathogenic", "review_status": "no assertion criteria provided", "review_date": 20160531, "origin": "somatic", "method": "literature only", "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "diseases": [ { "symbols": { "medgen": "C0279663" } } ], "accession_id": "SCV000504677" } ], "date_created": 20170308, "review_date": 20160531, "review_status": "no assertion criteria provided", "review_description": "Likely pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Ovarian serous cystadenocarcinoma", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV000429822", "allele_id": 27405, "clinical_significance": [ "Likely pathogenic" ], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "submitter_date": 20160718, "review_description": "Likely pathogenic", "review_status": "no assertion criteria provided", "review_date": 20160531, "origin": "somatic", "method": "literature only", "finding": [ { "symbols": { "medgen": "C0279680" } } ], "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "accession_id": "SCV000504680" } ], "date_created": 20170308, "finding": [ { "normalized_phenotype": [ "Transitional Cell Carcinoma Of The Bladder" ], "symbols": { "medgen": "C0279680", "mondo": "MONDO:0005611", "human_phenotype_ontology": "HP:0006740" }, "names": [ "Bladder Transitional Cell Carcinoma" ] } ], "review_date": 20160531, "review_status": "no assertion criteria provided", "review_description": "Likely pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Transitional cell carcinoma of the bladder", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV000430161", "diseases": [ { "normalized_disease": [ "Uterine Corpus Cancer" ], "symbols": { "medgen": "C0153574" }, "normalized_cancer": [ "Uterus" ], "names": [ "Uterine Corpus Cancer" ] } ], "allele_id": 27405, "clinical_significance": [ "Likely pathogenic" ], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "submitter_date": 20160718, "review_description": "Likely pathogenic", "review_status": "no assertion criteria provided", "review_date": 20160531, "origin": "somatic", "method": "literature only", "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "diseases": [ { "symbols": { "medgen": "C0153574" } } ], "accession_id": "SCV000504663" } ], "date_created": 20170308, "review_date": 20160531, "review_status": "no assertion criteria provided", "review_description": "Likely pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Malignant neoplasm of body of uterus", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV000433409", "diseases": [ { "pub_med": [ 24493721 ], "normalized_disease": [ "Cutaneous Melanoma", "Melanoma, Cutaneous Malignant, Susceptibility to, 1" ], "symbols": { "medgen": "C0151779", "mesh": "C562393", "mondo": "MONDO:0005012", "human_phenotype_ontology": "HP:0012056" }, "normalized_cancer": [ "Skin", "Malignant melanoma, somatic", "Cutaneous Melanoma" ], "names": [ "Cutaneous Melanoma", "Melanoma, Cutaneous Malignant, Susceptibility to, 1", "Cutaneous Melanoma" ] } ], "allele_id": 27405, "clinical_significance": [ "Likely pathogenic" ], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "submitter_date": 20160718, "review_description": "Likely pathogenic", "review_status": "no assertion criteria provided", "review_date": 20160531, "origin": "somatic", "method": "literature only", "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "diseases": [ { "symbols": { "mesh": "C562393" } } ], "accession_id": "SCV000504666" } ], "date_created": 20170308, "review_date": 20160531, "review_status": "no assertion criteria provided", "review_description": "Likely pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Malignant melanoma of skin", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV000436207", "diseases": [ { "normalized_disease": [ "Glioblastoma" ], "symbols": { "medgen": "C0017636", "mesh": "D005909", "mondo": "MONDO:0018177" }, "names": [ "Glioblastoma", "Giant Cell Glioblastoma (Histologic Variant)", "Gliosarcoma (Histologic Variant)" ] } ], "allele_id": 27405, "clinical_significance": [ "Likely pathogenic" ], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "submitter_date": 20160718, "review_description": "Likely pathogenic", "review_status": "no assertion criteria provided", "review_date": 20160531, "origin": "somatic", "method": "literature only", "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "diseases": [ { "symbols": { "mesh": "D005909" } } ], "accession_id": "SCV000504675" } ], "date_created": 20170308, "review_date": 20160531, "review_status": "no assertion criteria provided", "review_description": "Likely pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Glioblastoma", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "accession_id": "RCV000441169", "diseases": [ { "pub_med": [ 22918138, 23619274, 34131312 ], "normalized_disease": [ "Neoplasm" ], "symbols": { "medgen": "C0027651", "mesh": "D009369", "mondo": "MONDO:0005070", "human_phenotype_ontology": "HP:0006741" }, "normalized_cancer": [ "Neoplasm", "Neoplasms", "Neoplasm (disease)" ], "names": [ "Neoplasm", "Neoplasms", "Neoplasm" ], "keyword": "neoplasm" } ], "allele_id": 27405, "clinical_significance": [ "Likely pathogenic" ], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "submitter_date": 20160718, "review_description": "Likely pathogenic", "review_status": "no assertion criteria provided", "review_date": 20150714, "origin": "somatic", "method": "literature only", "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "diseases": [ { "symbols": { "mesh": "D009369" } } ], "accession_id": "SCV000504684" } ], "date_created": 20170308, "review_date": 20150714, "review_status": "no assertion criteria provided", "review_description": "Likely pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Neoplasm", "review_stars": 0, "submission_description": [], "variant_id": 10190170075771200004 }, { "variation_id": 12366, "variant_id": 10190170075771200004, "accession_id": "RCV000013164", "diseases": [ { "normalized_disease": [ "Thyroid Gland Undifferentiated (Anaplastic) Carcinoma" ], "symbols": { "medgen": "C0238461", "mondo": "MONDO:0006468", "human_phenotype_ontology": "HP:0011779" }, "normalized_cancer": [ "Thyroid", "Anaplastic Thyroid Cancer" ], "names": [ "Thyroid Gland Undifferentiated (Anaplastic) Carcinoma", "Thyroid Gland Undifferentiated (Anaplastic) Carcinoma", "Thyroid Gland Undifferentiated (Anaplastic) Carcinoma", "Thyroid Carcinoma, Anaplastic, Somatic" ], "keyword": "Neoplasm" } ], "allele_id": 27405, "clinical_significance": [ "Pathogenic" ], "submissions": [ { "submitter_name": "OMIM", "submission_description": [ "Malkin et al. (1992) identified a germline CGT-to-CAT mutation in exon 8 of the p53 gene that converted arg273 to his (R273H). The proband was a male in whom soft-tissue sarcoma was discovered at the age of 22 years and gastric carcinoma at the age of 30 years (see LFS; 151623).", "In 5 of 6 anaplastic carcinomas of the thyroid and in an anaplastic carcinoma thyroid cell line ARO, Fagin et al. (1993) identified the R273H mutation. The presence of p53 mutations almost exclusively in poorly differentiated thyroid tumors and thyroid cancer cell lines suggested that inactivation of p53 may confer these neoplasms with aggressive properties and may further loss of differentiated function." ], "submitter_date": 20130409, "review_description": "Pathogenic", "review_status": "no assertion criteria provided", "review_date": 19930101, "origin": "somatic", "pub_med_references": [ 1565144, 8423216 ], "method": "literature only", "date_updated": 20130408, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "normalized_cancer": [ "Anaplastic Thyroid Cancer" ], "names": [ "Thyroid Carcinoma, Anaplastic, Somatic" ] } ], "accession_id": "SCV000033411" } ], "date_created": 20130404, "review_date": 19930101, "review_status": "no assertion criteria provided", "pub_med_references": [ 1565144, 8423216 ], "review_description": "Pathogenic", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Thyroid gland undifferentiated (anaplastic) carcinoma", "review_stars": 0, "submission_description": [ "Malkin et al. (1992) identified a germline CGT-to-CAT mutation in exon 8 of the p53 gene that converted arg273 to his (R273H). The proband was a male in whom soft-tissue sarcoma was discovered at the age of 22 years and gastric carcinoma at the age of 30 years (see LFS; 151623).", "In 5 of 6 anaplastic carcinomas of the thyroid and in an anaplastic carcinoma thyroid cell line ARO, Fagin et al. (1993) identified the R273H mutation. The presence of p53 mutations almost exclusively in poorly differentiated thyroid tumors and thyroid cancer cell lines suggested that inactivation of p53 may confer these neoplasms with aggressive properties and may further loss of differentiated function." ] }, { "variation_id": 12366, "variant_id": 10190170075771200004, "submission_description": [], "review_status": "no assertion criteria provided", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Malignant tumor of breast", "review_description": "Pathogenic", "finding": [ { "pub_med_references": [ 26389210, 26389258, 29939840, 30452337, 31479144 ], "symbols": { "medgen": "C0006142", "mondo": "MONDO:0007254" }, "names": [ "Breast Cancer", "Breast Cancer", "Breast Cancer" ], "disease_mechanism": "loss of function" } ], "date_created": 20210413, "submissions": [ { "submitter_name": "Department of Pathology and Laboratory Medicine, Sinai Health System", "submission_description": [ "The TP53 p.Arg273His variant was identified in 2 of 942 proband chromosomes (frequency: 0.002) from individuals or families with Li Fraumeni Syndrome or thyroid cancer (Masciari 2011, Romei 2017) and reported in multiple case studies in individuals or families with Li-Fraumeni Syndrome (Bemis 2007, Sugawara 2011, Baumuller 2010). In addition, the variant was reported as a somatic mutation in breast cancer, colorectal cancer, non-small cell lung cancer or high-grade glioma tissues (Jiang 2018, Heath-2018, Li 2018). The variant was also identified in dbSNP (ID: rs28934576) as \"With Pathogenic allele\", ClinVar (classified as pathogenic by Invitae, GeneDx, Ambry Genetics and eight other submitters; as likely pathogenic by two submitters), and in LOVD 3.0 (2x as pathogenic). The variant was identified in control databases in 4 of 245868 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 3 of 111470 chromosomes (freq: 0.00003), Ashkenazi Jewish in 1 of 9842 chromosomes (freq: 0.0001), but not in the African, Other, Latino, East Asian, Finnish, or South Asian populations. Several functional studies suggests the variant enhances cell migration, invasion abilities, influences apoptosis, leads to more aggressive phenotypes, and enhances cancer cell malignancy (Kang 2018, Joerger 2010, Dong 2007, Li 2014). The p.Arg273 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic." ], "submitter_date": 20210331, "review_description": "Pathogenic", "review_status": "no assertion criteria provided", "origin": "unknown", "method": "clinical testing", "date_updated": 20210413, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "symbols": { "mondo": "MONDO:0007254" } } ], "accession_id": "SCV001554107" } ], "clinical_significance": [ "Pathogenic" ], "review_stars": 0, "allele_id": 27405, "accession_id": "RCV001358389" }, { "variation_id": 12366, "variant_id": 10190170075771200004, "submission_description": [], "review_status": "criteria provided, single submitter", "title": "NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Squamous cell carcinoma of the head and neck", "review_description": "Pathogenic", "date_created": 20170308, "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "submitter_date": 20160718, "review_description": "Likely pathogenic", "review_status": "no assertion criteria provided", "review_date": 20160531, "origin": "somatic", "method": "literature only", "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "diseases": [ { "symbols": { "mesh": "C535575" } } ], "accession_id": "SCV000504662" }, { "submitter_name": "Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo", "submission_description": [], "submitter_date": 20201208, "review_description": "Pathogenic", "review_status": "criteria provided, single submitter", "origin": "somatic", "method": "case-control", "date_updated": 20201212, "clinical_significance": [ "Pathogenic" ], "diseases": [ { "symbols": { "omim": "275355" } } ], "accession_id": "SCV001450494" } ], "clinical_significance": [ "Pathogenic" ], "review_stars": 1, "allele_id": 27405, "diseases": [ { "normalized_disease": [ "Head and Neck Squamous Cell Carcinoma" ], "symbols": { "orphanet": "67037", "omim": "275355", "medgen": "C1168401", "mesh": "D000077195", "mondo": "MONDO:0010150" }, "normalized_cancer": [ "Head and Neck Squamous Cell Carcinoma" ], "names": [ "Head and Neck Squamous Cell Carcinoma", "Head and Neck Squamous Cell Carcinoma", "Head and Neck Squamous Cell Carcinoma", "Head and Neck Squamous Cell Carcinoma" ], "keyword": "Hereditary cancer syndrome" } ], "accession_id": "RCV000422097" } ], "main_data": "pathogenic **3**", "names": [ "NM_000546.6(TP53):c.818G>A (p.Arg273His)", "p.R273H:CGT>CAT" ], "variant_type": "SNV" } ], "icgc_somatic": [ { "version": "release 28", "affected_donors": 182, "mutation_id": "MU24637", "project_code": [ { "key": "ESAD-UK", "value": 16 }, { "key": "UCEC-US", "value": 12 }, { "key": "BRCA-US", "value": 12 }, { "key": "COAD-US", "value": 12 }, { "key": "OV-US", "value": 12 }, { "key": "LGG-US", "value": 11 }, { "key": "STAD-US", "value": 10 }, { "key": "COCA-CN", "value": 10 }, { "key": "PACA-CA", "value": 9 }, { 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"molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Breast Cancer", "doid": "1612", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/398", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In breast cancer patients harboring TP53 mutation, mutations in DNA contact regions such as R273 are prognostic for a worse relapse-free survival compared to other non-silent mutations in TP53.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:28 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 9569050 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "R273H", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/122", "molecular_profiles": null }, { "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/4882", "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 R273H loss of function mutation is present in 7 cell lines and all are insensitive to MDM2 Inhibitor AMGMDS3.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:28 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 25730903 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "R273H", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/122", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Osteosarcoma", "doid": "3347", "drug_interaction_type": null, "drugs": [ "Methotrexate", "Doxorubicin" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/7430", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "Several preclinical studies were testing drug resistance mechanisms of TP53-R273H variant. Saos-2 cells were transfected with TP53-R273H mutation and these cells were used in the study. Using a western blot, Saos-2/TP53-R273H cells were shown to have a 0.6-fold down-regulation (compared to the Control) for Procaspase-3 protein expression. In addition, Saos-2/TP53-R273H cells were shown to be more resistant to methotrexate and doxorubicin. Reduced levels of drug-induced apoptosis were seen in Saos-2/TP53-R273H cells treated with doxorubicin (0.05 uM and 0.10 uM) and methotrexate (25 nM and 50 nM) in DNA fragmentation assays. According to the results, TP53-R273H induces drug resistance when procaspase-3 is down-regulated.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "TP53", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:28 UTC", "nct_ids": null, "normalized_drug": [ "Doxorubicin, Methotrexate" ], "phenotypes": null, "pub_med_references": [ 17363498 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "R273H", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/122", "molecular_profiles": null }, { "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/7530", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "The R273H mutation was used to create isogenic AML cell lines using MOLM13 and K526 lines. R273H/- 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, including R273H. RNAseq studies determined that a novel gene expression program was not induced in R273H 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 R273H 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 21:46:28 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 31395785 ], "rating": "4", "representative_transcript": null, "transcripts": null, "variant": "R273H", "variant_civic_url": null, "variant_origin": "Unknown", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/122", "molecular_profiles": null } ] } ], "nih_gdc": [ { "version": "08-Dec-2023", "sex": [ { "key": "Female", "value": 40 }, { "key": "Male", "value": 21 } ], "age_freq": [ { "key": "60-70", "value": 16 }, { "key": "50-60", "value": 15 }, { "key": "70-80", "value": 11 }, { "key": "40-50", "value": 9 }, { "key": "80-90", "value": 5 }, { "key": "30-40", "value": 4 }, { "key": "20-30", "value": 1 } ], "os_status": [ { "key": "Living", "value": 48 }, { "key": "Deceased", "value": 13 } ], "race": [ { "key": "European (non-Finnish)", "value": 46 }, { "key": "African", "value": 5 }, { "key": "Latino", "value": 3 } ], "tumor_status": [ { "key": "Disease Free", "value": 34 }, { "key": "Recurred", "value": 23 } ], "tumor_tissue_site": null, "path_t_stage": [ { "key": "T3", "value": 16 }, { "key": "T2", "value": 12 }, { "key": "T1", "value": 5 }, { "key": "T2B", "value": 1 }, { "key": "T4", "value": 1 }, { "key": "T4A", "value": 1 } ], "path_n_stage": [ { "key": "N0", "value": 15 }, { "key": "N1", "value": 5 }, { "key": "N2", "value": 4 }, { "key": "N0 (I-)", "value": 2 }, { "key": "N1A", 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"No", "value": 46 }, { "key": "Yes", "value": 3 } ], "drug": null, "measure_of_response": [ { "key": "Complete Response", "value": 8 }, { "key": "Clinical Progressive Disease", "value": 6 }, { "key": "Stable Disease", "value": 1 } ], "therapy_type": [ { "key": "Chemotherapy", "value": 89 }, { "key": "Hormone Therapy", "value": 4 }, { "key": "Targeted Molecular Therapy", "value": 4 }, { "key": "Chemotherapy|Hormone Therapy", "value": 1 } ], "route_of_administration": [ { "key": "Iv", "value": 48 }, { "key": "Po", "value": 11 }, { "key": "Ip|Iv", "value": 4 }, { "key": "Ip", "value": 2 } ], "therapy_ongoing": [ { "key": "NO", "value": 92 }, { "key": "YES", "value": 6 } ], "clinical_significance": [ { "key": "Likely Pathogenic", "value": 96 }, { "key": "Pathogenic", "value": 96 }, { "key": "Pathogenic/Likely Pathogenic", "value": 96 } ], "pub_med_references": [ 1565144, 8423216, 9569050, 15390294, 15951970, 16489069, 17606709, 18511570, 23161690, 24381225, 24487413, 24641375, 25105660, 25157968, 26619011, 26716509, 26884312, 26900293, 28854261, 31882575, 32039725 ], "oncotree_code": [ { "key": "OVARY", "value": 9 }, { "key": "COAD", "value": 6 }, { "key": "HNSC", "value": 6 }, { "key": "READ", "value": 5 }, { "key": "ASTR", "value": 4 }, { "key": "BOWEL", "value": 3 }, { "key": "GBM", "value": 3 }, { "key": "LUSC", "value": 3 }, { "key": "OAST", "value": 2 }, { "key": "STAD", "value": 2 }, { "key": "BREAST", "value": 1 }, { "key": "HCC", "value": 1 }, { "key": "ODG", "value": 1 }, { "key": "STOMACH", "value": 1 } ], "cancer_name": [ { "key": "Serous Cystadenocarcinoma", "value": 9 }, { "key": "Infiltrating Ductal Carcinoma", "value": 7 }, { "key": "Colon Adenocarcinoma", "value": 6 }, { "key": "Head & Neck Squamous Cell Carcinoma", "value": 6 }, { "key": "Rectal Adenocarcinoma", "value": 5 }, { "key": "Astrocytoma", "value": 4 }, { "key": "Serous endometrial adenocarcinoma", "value": 4 }, { "key": "Untreated primary (de novo) GBM", "value": 3 }, { "key": "Lung Squamous Cell Carcinoma- Not Otherwise Specified (NOS)", "value": 3 }, { "key": "Colon Mucinous Adenocarcinoma", "value": 3 }, { "key": "Oligoastrocytoma", "value": 2 }, { "key": "Endometrioid endometrial adenocarcinoma", "value": 2 }, { "key": "Stomach, Adenocarcinoma, Not Otherwise Specified (NOS)", "value": 2 }, { "key": "Mixed Histology (please specify)", "value": 1 }, { "key": "Oligodendroglioma", "value": 1 }, { "key": "Infiltrating Lobular Carcinoma", "value": 1 }, { "key": "Hepatocellular Carcinoma", "value": 1 }, { "key": "Stomach, Intestinal Adenocarcinoma, Tubular Type", "value": 1 } ], "cancer_type": [ { "key": "Colorectal Cancer", "value": 11 }, { "key": "Glioma", "value": 10 }, { "key": "Ovarian/Fallopian Tube Cancer, NOS", "value": 9 }, { "key": "Infiltrating Ductal Carcinoma", "value": 7 }, { "key": "Head and Neck Cancer", "value": 6 }, { "key": "Serous endometrial adenocarcinoma", "value": 4 }, { "key": "Bowel Cancer, NOS", "value": 3 }, { "key": "Non-Small Cell Lung 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"NCBI ClinVar2": [ { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": true, "acmg_class": "Pathogenic", "acmg_reannotated": "Pathogenic", "source": "NCBI ClinVar2", "codon": 273, "gene_symbol": "TP53", "hgvs": "R273H", "transcript": "ENST00000269305.4", "submission_count": 59, "review_stars": 3, "accession_count": 38, "publication_count": 50, "clinical_significance": [ "pathogenic" ], "pub_med_references": [ 26681312, 27374712, 28453743, 28873162, 29489754, 29979965, 30224644, 30816478, 31882575, 33372952, 36988593 ], "disease_name": [ "Acute Myeloid Leukemia", "Acute Myeloid Leukemia, Adult", "Adrenal Cortex Carcinoma", "Adrenocortical Carcinoma, Hereditary", "Adult Hepatocellular Carcinoma" ] } ], "Saphetor VarSome Comment": [ { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": true, "acmg_class": "Pathogenic", "acmg_reannotated": "Pathogenic", "source": "Saphetor VarSome Comment", "codon": 273, "gene_symbol": "TP53", "hgvs": "R273H", "transcript": "ENST00000269305.4", "comment": "IARC_TA class: non-functional, IARC_Somatic count: 858, IARC_validated SNP: NO\n", "flagged_at_timestamp": "2018-02-06 13:13:57", "id": 1876, "saphetorClass": "pathogenic", "user_id": 2582, "variant_id": 10190170075771200004 } ], "Saphetor PubMedUserEntry": [ { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": false, "acmg_class": "Uncertain Significance", "acmg_reannotated": "Pathogenic", "source": "Saphetor PubMedUserEntry", "codon": 273, "gene_symbol": "TP53", "hgvs": "R273H", "transcript": "ENST00000269305.4", "pub_med_references": [ 33131904 ], "pathogenicity": "DR", "id": 28133, "confirmedByFunctionalStudy": false }, { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": true, "acmg_class": "Pathogenic", "acmg_reannotated": "Pathogenic", "source": "Saphetor PubMedUserEntry", "codon": 273, "gene_symbol": "TP53", "hgvs": "R273H", "transcript": "ENST00000269305.4", "pub_med_references": [ 33990091 ], "pathogenicity": "P", "id": 25453, "confirmedByFunctionalStudy": false }, { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": true, "acmg_class": "Pathogenic", "acmg_reannotated": "Pathogenic", "source": "Saphetor PubMedUserEntry", "codon": 273, "gene_symbol": "TP53", "hgvs": "R273H", "transcript": "ENST00000269305.4", "pub_med_references": [ 24677579 ], "pathogenicity": "P", "id": 23957, "confirmedByFunctionalStudy": true }, { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": false, "acmg_class": "Uncertain Significance", "acmg_reannotated": "Pathogenic", "source": "Saphetor PubMedUserEntry", "codon": 273, "gene_symbol": "TP53", "hgvs": "R273H", "transcript": "ENST00000269305.4", "pub_med_references": [ 30126368 ], "id": 22820, "confirmedByFunctionalStudy": false }, { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": false, "acmg_class": "Uncertain Significance", "acmg_reannotated": "Pathogenic", "source": "Saphetor PubMedUserEntry", "codon": 273, "gene_symbol": "TP53", "hgvs": "R273H", "transcript": "ENST00000269305.4", "pub_med_references": [ 30723117 ], "id": 22819, "confirmedByFunctionalStudy": false }, { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": false, "acmg_class": "Uncertain Significance", "acmg_reannotated": "Pathogenic", "source": "Saphetor PubMedUserEntry", "codon": 273, "gene_symbol": "TP53", "hgvs": "R273H", "transcript": "ENST00000269305.4", "pub_med_references": [ 32054657 ], "pathogenicity": "DA", "id": 21122, "confirmedByFunctionalStudy": false }, { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": true, "acmg_class": "Pathogenic", "acmg_reannotated": "Pathogenic", "source": "Saphetor PubMedUserEntry", "codon": 273, "gene_symbol": "TP53", "hgvs": "R273H", "transcript": "ENST00000269305.4", "pub_med_references": [ 29026176 ], "pathogenicity": "P", "id": 5843, "confirmedByFunctionalStudy": false }, { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": true, "acmg_class": "Pathogenic", "acmg_reannotated": "Pathogenic", "source": "Saphetor PubMedUserEntry", "codon": 273, "gene_symbol": "TP53", "hgvs": "R273H", "transcript": "ENST00000269305.4", "pub_med_references": [ 26466571 ], "pathogenicity": "P", "id": 5825, "confirmedByFunctionalStudy": false }, { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": true, "acmg_class": "Pathogenic", "acmg_reannotated": "Pathogenic", "source": "Saphetor PubMedUserEntry", "codon": 273, "gene_symbol": "TP53", "hgvs": "R273H", "transcript": "ENST00000269305.4", "pub_med_references": [ 29522266 ], "pathogenicity": "P", "id": 4419, "confirmedByFunctionalStudy": false }, { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": true, "acmg_class": "Pathogenic", "acmg_reannotated": "Pathogenic", "source": "Saphetor PubMedUserEntry", "codon": 273, "gene_symbol": "TP53", "hgvs": "R273H", "transcript": "ENST00000269305.4", "pub_med_references": [ 30126368 ], "pathogenicity": "P", "id": 22820, "confirmedByFunctionalStudy": false, "is_lifted_over": true, "lifted_from": "chr17:7673802 C⇒T" }, { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": true, "acmg_class": "Pathogenic", "acmg_reannotated": "Pathogenic", "source": "Saphetor PubMedUserEntry", "codon": 273, "gene_symbol": "TP53", "hgvs": "R273H", "transcript": "ENST00000269305.4", "pub_med_references": [ 30723117 ], "pathogenicity": "P", "id": 22819, "confirmedByFunctionalStudy": false, "is_lifted_over": true, "lifted_from": "chr17:7673802 C⇒T" } ], "UNIPROT UniProt Variants": [ { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": true, "acmg_class": "Pathogenic", "acmg_reannotated": "Pathogenic", "source": "UNIPROT UniProt Variants", "codon": 273, "gene_symbol": "TP53", "hgvs": "R273H", "transcript": "ENST00000269305.4", "possible_functional_studies": [ 7682763, 8378080, 8495424, 8826941, 8995554, 9115587, 10567903, 10570149, 10671690, 10690522, 10918210, 11051241, 11229518, 11244334, 11297255, 12118317, 12509970, 15017592, 15057748, 15138567, 15161705, 15308588, 16322298, 16890317, 17388661, 17692090, 21559688, 22361929, 23103869 ], "pub_med_references": [ 23525077, 23619168, 23700467, 23852799, 23917401, 23960188, 24140581, 24375041, 24936796, 24942490, 31882575 ], "disease_name": [ "Acute myeloid leukemia", "Adrenal cortex carcinoma", "Adrenocortical carcinoma, hereditary", "B-cell chronic lymphocytic leukemia", "Basal cell carcinoma, susceptibility to, 7" ], "annotation_id": "VAR_005995" } ] } } ] } ], "acmg_annotation": { "version_name": "11.14.0", "gene_symbol": "TP53", "transcript": "ENST00000269305.4", "transcript_reason": "MANE select", "coding_impact": "missense", "blosum_score": -1, "verdict": { "ACMG_rules": { "benign_score": 0, "benign_subscore": "Uncertain Significance", "clinical_score": 5.27, "pathogenic_score": 20, "pathogenic_subscore": "Pathogenic", "total_score": 20, "verdict": "Pathogenic" }, "classifications": [ "PP5_Very Strong", "PM1_Strong", "PM5_Strong", "PP3_Moderate", "PS3_Supporting", "PM2_Supporting" ] }, "classifications": [ { "name": "PP5", "met_criteria": true, "user_explain": [ "Combined evidence strength is Very Strong (score = 10).", "Very Strong: ClinVar classifies this variant as Pathogenic, 3 stars (reviewed Jan '24, 59 submissions of which 3 are from high confidence submitters), citing 11 articles (%%PUBMED:36988593%%, %%PUBMED:33372952%%, %%PUBMED:31882575%%, %%PUBMED:30816478%%, %%PUBMED:30224644%% and 6 more).", "Moderate: the VarSome community has classified this variant as Pathogenic, citing 6 articles (%%PUBMED:33990091%%, %%PUBMED:30723117%%, %%PUBMED:30126368%%, %%PUBMED:29522266%%, %%PUBMED:29026176%% and %%PUBMED:26466571%%)." ], "strength": "Very Strong" }, { "name": "PM1", "met_criteria": true, "user_explain": [ "Hot-spot of length 17 amino-acids has 125 missense/in-frame variants (50 pathogenic variants, 75 uncertain variants and no benign), which qualifies as strong pathogenic.", "UniProt protein P53_HUMAN region of interest 'Interaction with DNA' has 63 missense/in-frame variants (28 pathogenic variants, 35 uncertain variants and no benign), which qualifies as moderate pathogenic.", "UniProt protein P53_HUMAN DNA-binding domain 'DNA-binding region_102-292' has 1 272 missense/in-frame variants (353 pathogenic variants, 914 uncertain variants and 5 benign variants), which qualifies as supporting pathogenic.", "UniProt protein P53_HUMAN region of interest 'Interaction with AXIN1' has 1 203 missense/in-frame variants (331 pathogenic variants, 868 uncertain variants and 4 benign variants), which qualifies as supporting pathogenic.", "UniProt protein P53_HUMAN region of interest 'Interaction with E4F1' has 271 missense/in-frame variants (78 pathogenic variants, 192 uncertain variants and 1 benign variant), which qualifies as supporting pathogenic.", "UniProt protein P53_HUMAN region of interest 'Required for interaction with ZNF385A' has 1 322 missense/in-frame variants (354 pathogenic variants, 963 uncertain variants and 5 benign variants), which qualifies as supporting pathogenic.", "UniProt protein P53_HUMAN region of interest 'Interaction with CCAR2' has 1 706 missense/in-frame variants (362 pathogenic variants, 1 308 uncertain variants and 36 benign variants), which qualifies as supporting pathogenic.", "UniProt protein P53_HUMAN region of interest 'Interaction with HIPK1' has 1 614 missense/in-frame variants (377 pathogenic variants, 1 203 uncertain variants and 34 benign variants), which qualifies as supporting pathogenic." ], "strength": "Strong" }, { "name": "PM5", "met_criteria": true, "user_explain": [ "Alternative variant ##chr17:7577121 G⇒T## (Arg273Ser) is classified Pathogenic, 2 stars, by ClinVar (confirmed using the germline classifier).", "Alternative variant ##chr17:7577121 G⇒C## (Arg273Gly) is classified Pathogenic, 2 stars, by ClinVar (confirmed using the germline classifier).", "Alternative variant ##chr17:7577121 G⇒A## (Arg273Cys) is classified Pathogenic by UniProt Variants (confirmed using the germline classifier).", "Alternative variant ##chr17:7577120 C⇒G## (Arg273Pro) is classified Likely Pathogenic by the VarSome community (confirmed using the germline classifier).", "Alternative variant ##chr17:7577120 C⇒A## (Arg273Leu) is classified Pathogenic by UniProt Variants (confirmed using the germline classifier).", "5 pathogenic alternative variants identified." ], "strength": "Strong" }, { "name": "PP3", "met_criteria": true, "user_explain": [ "MetaRNN = 0.851 is between 0.841 and 0.939 ⇒ moderate pathogenic." ], "strength": "Moderate" }, { "name": "PS3", "met_criteria": true, "user_explain": [ "Combined evidence strength is Supporting (score = 1).", "Supporting: UniProt Variants classifies this variant as Pathogenic, backed by functional studies (requires user validation) mentioned in 29 articles (%%PUBMED:23103869%%, %%PUBMED:22361929%%, %%PUBMED:21559688%%, %%PUBMED:17692090%%, %%PUBMED:17388661%% and 24 more), and also citing 11 articles (%%PUBMED:31882575%%, %%PUBMED:24942490%%, %%PUBMED:24936796%%, %%PUBMED:24375041%%, %%PUBMED:24140581%% and 6 more)." ], "strength": "Supporting" }, { "name": "PM2", "met_criteria": true, "user_explain": [ "Variant not found in gnomAD genomes, good gnomAD genomes coverage = 30.7.", "GnomAD exomes homozygous allele count = 0 is less than 2 for AD/AR gene TP53, good gnomAD exomes coverage = 71.7." ], "strength": "Supporting" } ], "gene_id": 33956, "sample_findings": { "phenotypes": "No matching phenotype found for gene TP53 which is associated with Adrenal Cortex Carcinoma, Adrenal Cortical Carcinoma, 202300, Adrenal, Breast, Brain, And Lung Sarcoma, Gastrointestinal Cancers, Breast Cancer, Osteosarcoma, Soft Tissue Sarcomas, Brain Tumors, Adrenocortical Carcinoma, Adrenocortical Carcinoma, Hereditary and 40 more, according to CGD, ClinGen Disease Validity, GenCC, Mondo, PanelApp and gene2phenotype.", "mode_of_inheritance": "AD/AR, based on gene information from CGD, ClinGen Disease Validity, GenCC, Mondo, PanelApp and gene2phenotype." } }, "amp_annotation": { "version_name": "11.14.0", "verdict": { "tier": "Tier II", "approx_score": 2.345 }, "classifications": [ { "name": "Crtd", "tier": "Tier I", "user_explain": { "Tier I": [ "ClinVar classifies this variant as Pathogenic, rated 3 stars related to the following 59 cancers: Acute Myeloid Leukemia, Acute granulocytic leukemia, Acute myelogenous leukemia, Acute non-lymphocytic leukemia, Adrenal cortex carcinoma and 54 more, with 31 somatic submissions, citing 50 articles (%%PUBMED:36988593%%, %%PUBMED:33372952%%, %%PUBMED:31882575%%, %%PUBMED:30816478%%, %%PUBMED:30224644%% and 45 more)." ], "Tier II": [ "DoCM reports 25 entries classified Tier II citing 7 articles (%%PUBMED:26619011%%, %%PUBMED:25157968%%, %%PUBMED:24641375%%, %%PUBMED:24487413%%, %%PUBMED:24381225%% and 2 more) related to the following 23 cancers: Acute Myeloid Leukemia, Adrenocortical Carcinoma, Bladder/Urinary Tract, Bowel and 18 more.", "CIViC reports 5 entries, 3 x 3-star and 2 x 4-star rated , listing 1 drug: \"Doxorubicin, Methotrexate\" related to the following 3 cancers: Breast, Cancer and Osteosarcoma." ] }, "approx_score": 3.2 }, { "name": "Drug", "tier": "Tier II", "user_explain": { "Tier II": [ "Cisplatin, Etoposide and Mitomycin (curated), reported by CIViC, related to Esophagus/Stomach - but no patient cancer type was provided for matching.", "Doxorubicin and Tamoxifen (curated), reported by CIViC, related to Breast - but no patient cancer type was provided for matching.", "Docetaxel and Docetaxel, Selumetinib (curated), reported by CIViC, related to Lung - but no patient cancer type was provided for matching.", "Pazopanib and Vorinostat (curated), reported by CIViC, related to Solid Tumor - but no patient cancer type was provided for matching.", "Capecitabine, Cetuximab, Oxaliplatin (curated), reported by CIViC, related to Bowel - but no patient cancer type was provided for matching.", "Carboplatin, Cisplatin (curated), reported by CIViC, related to Ovary/Fallopian Tube - but no patient cancer type was provided for matching." ] }, "approx_score": 5.0 }, { "name": "Germ", "tier": "Tier I", "user_explain": { "Tier I": [ "This variant is classified Pathogenic, by the germline classifier rules PP5_Very Strong, PM1_Strong, PM5_Strong, PP3_Moderate, PS3_Supporting and PM2_Supporting." ] }, "approx_score": 3.1 }, { "name": "Soma", "tier": "Tier I", "user_explain": { "Tier I": [ "This variant is reported in 3 103 out of the 42 872 somatic samples for gene TP53, which has 5 872 reported somatic variants. Its GnomAD ƒ = 0.0000159. This is statistically rated Tier I." ] }, "total_samples": 3103, "approx_score": 2.0 }, { "name": "Pubs", "tier": "Tier I", "user_explain": { "Tier I": [ "VarSome users have linked 7 articles stating the variant is pathogenic (%%PUBMED:33990091%%, %%PUBMED:30723117%%, %%PUBMED:30126368%%, %%PUBMED:29522266%%, %%PUBMED:29026176%% and 2 more)(2 entries have been automatically lifted over from hg38)." ] }, "approx_score": 3.0 }, { "name": "Path", "tier": "Tier I", "user_explain": { "Tier I": [ "The Human Protein Atlas classifies TP53 as tumour-suppressing." ], "Tier II": [ "BioCarta associates gene TP53 with the following 4 cancers: Breast, RB Tumor Suppressor/Checkpoint Signaling in response to DNA damage, Role of BRCA1, BRCA2 and ATR in Cancer Susceptibility and Tumor Suppressor Arf Inhibits Ribosomal Biogenesis.", "Consensus associates gene TP53 with the following 31 cancers: Adenoid Cystic Carcinoma, Basal Cell Carcinoma, Bladder/Urinary Tract, Breast, CNS/Brain and 26 more.", "GHR reports that the TP53 gene provides instructions for making a protein called tumor protein p53 (or p53). Also, associates TP53 with the following 9 cancers: Bladder/Urinary Tract, Breast, Cholangiocarcinoma, Head and Neck Squamous Cell Carcinoma, Li-Fraumeni Syndrome and 4 more.", "KEGG reports that gene TP53 is involved in MAPK signaling pathway, Wnt signaling pathway and p53 signaling pathway. Also, associates TP53 with the following 12 cancers: Basal Cell Carcinoma, Bladder/Urinary Tract, Colorectal cancer, Endometrial cancer, Glioma and 7 more.", "Mondo associates gene TP53 with the following 9 cancers: B-Cell Chronic Lymphocytic Leukemia, Bone Osteosarcoma, Choroid Plexus Carcinoma, Choroid Plexus Papilloma, Hepatocellular Carcinoma and 4 more." ] }, "approx_score": 4.0 }, { "name": "Type", "tier": "Tier III", "user_explain": { "Tier III": [ "ACMG rule PVS1 did not trigger.", "ACMG rule PM4 did not trigger.", "Variant is not predicted splicing: no prediction from MaxEntScan." ] }, "approx_score": 2.0 }, { "name": "Freq", "tier": "Tier II", "user_explain": { "Tier II": [ "ACMG rule PM2 was triggered with strength Supporting: Variant not found in gnomAD genomes, good gnomAD genomes coverage = 30.7.\nGnomAD exomes homozygous allele count = 0 is less than 2 for AD/AR gene TP53, good gnomAD exomes coverage = 71.7." ] }, "approx_score": 2.0 }, { "name": "Pred", "tier": "Tier III", "user_explain": { "Tier III": [ "Uncertain Significance computational verdict based on 1 pathogenic prediction from MetaRNN, conflicting with no benign predictions (and 1 uncertain prediction from DANN)." ] }, "approx_score": 1.0 } ] }, "cbio_portal": [ { "version": "06-Jun-2023", "total_samples": 1572, "sample_id": null, "sample_type": [ { "key": "Primary", "value": 877 }, { "key": "Metastasis", "value": 393 }, { "key": "Metastatic", "value": 14 }, { "key": "Recurrence", "value": 12 }, { "key": "First Recurrence", "value": 4 }, { "key": "Recurrent", "value": 3 }, { "key": "Tumor Primary", "value": 3 }, { "key": "Local Recurrence", "value": 2 }, { "key": "Primary Tumour", "value": 1 }, { "key": "Unknown Tumor", "value": 1 } ], "study_name": null, "mutation_status": [ { "key": "Somatic", "value": 829 }, { "key": "Somatic_Vs_Pool", "value": 3 }, { "key": "Germline", "value": 1 }, { "key": "None", "value": 1 } ], "validation_status": [ { "key": "Untested", "value": 75 }, { "key": "Valid", "value": 37 }, { "key": "Not_Done", "value": 8 }, { "key": "High", "value": 3 }, { "key": "Validated", "value": 3 }, { "key": "Wildtype", "value": 1 }, { "key": "__Unknown__,Valid,Valid", "value": 1 } ], "center": [ { "key": "Mskcc", "value": 666 }, { "key": "Broad.Mit.Edu", "value": 67 }, { "key": "Genome.Wustl.Edu", "value": 65 }, { "key": "Hgsc.Bcm.Edu", "value": 23 }, { "key": "Metabric", "value": 18 }, { "key": "Fhcrc", "value": 11 }, { "key": "Mdanderson.Org/Ucsc.Edu/Broad.Mit.Edu", "value": 9 }, { "key": "Qcmg.Uq.Edu.Au", "value": 8 }, { "key": "Hgsc.Bcm.Edu;Broad.Mit.Edu;Ucsc.Edu", "value": 8 }, { "key": "Ohsu.Edu", "value": 8 }, { "key": "Mskcc-Cmo", "value": 7 }, { "key": "Genome.Wustl.Edu;Unc.Edu", "value": 7 }, { "key": "Mskcc.Org", "value": 5 }, { "key": "Discover.Nci.Nih.Gov", "value": 5 }, { "key": "University Of Michigan", "value": 5 }, { "key": "Msk-Impact410", "value": 4 }, { "key": "Bgi", "value": 4 }, { "key": "Mdanderson.Org/Broad.Mit.Edu", "value": 4 }, { "key": "Papaemmanuil_Nejm_2016", "value": 3 }, { "key": "Ut Southwestern", "value": 3 }, { "key": "Genentech", "value": 3 }, { "key": "Baylor College Of Medicine", "value": 3 }, { "key": "Msk-Impact", "value": 2 }, { "key": "Grail", "value": 2 }, { "key": "Gr", "value": 2 }, { "key": "Foundation", "value": 2 }, { "key": "Ucsf", "value": 1 }, { "key": "Unc.Edu", "value": 1 }, { "key": "Ucologne", "value": 1 }, { "key": "St. Jude", "value": 1 }, { "key": "Utokyo", "value": 1 }, { "key": "Wcm", "value": 1 }, { "key": "Omrf.Org", "value": 1 }, { "key": "Msk-Impact468", "value": 1 }, { "key": "Msk-Hemepact_V3", "value": 1 }, { "key": "John Hopkins", "value": 1 }, { "key": "Jhu", "value": 1 }, { "key": "Http://Www.Wuxiapptec.Com", "value": 1 }, { "key": "Hgsc.Bcm.Edu;Broad.Mit.Edu", "value": 1 }, { "key": "Cpcgene", "value": 1 }, { "key": "Bc", "value": 1 } ], "t_ref_count": 574014, "t_alt_count": 263489, "n_ref_count": 514786, "n_alt_count": 659, "n_depth": 35262, "t_depth": 66408, "canonical": true, "hotspot": false, "ensp": "ENSP00000269305", "ccds": "CCDS11118.1", "cdsposition": "818", "cdnaposition": "1008", "biotype": "Protein_Coding", "uniparc": "UPI000002ED67", "pick": 1.0, "sex": [ { "key": "Female", "value": 745 }, { "key": "Male", "value": 716 } ], "age_freq": [ { "key": "60-70", "value": 124 }, { "key": "50-60", "value": 120 }, { "key": "70-80", "value": 84 }, { "key": "40-50", "value": 65 }, { "key": "30-40", "value": 25 }, { "key": "80-90", "value": 24 }, { "key": "20-30", "value": 15 }, { "key": "10-20", "value": 8 }, { "key": "1-5", "value": 3 }, { "key": "5-10", "value": 2 } ], "os_months": [ { "key": "13", "value": 55 }, { "key": "3", "value": 45 }, { "key": "1", "value": 36 }, { "key": "0", "value": 36 }, { "key": "12", "value": 33 }, { "key": "16", "value": 32 }, { "key": "2", "value": 31 }, { "key": "7", "value": 31 }, { "key": "9", "value": 30 }, { "key": "6", "value": 27 }, { "key": "18", "value": 26 }, { "key": "20", "value": 25 }, { "key": "15", "value": 25 }, { "key": "22", "value": 24 }, { "key": "10", "value": 23 }, { "key": "17", "value": 22 }, { "key": "8", "value": 22 }, { "key": "19", "value": 21 }, { "key": "26", "value": 20 }, { "key": "30", "value": 19 }, { "key": "11", "value": 19 }, { "key": "46", "value": 17 }, { "key": "14", "value": 16 }, { "key": "5", "value": 16 }, { "key": "32", "value": 16 }, { "key": "24", "value": 16 }, { "key": "4", "value": 15 }, { "key": "25", "value": 15 }, { "key": "29", "value": 14 }, { "key": "28", "value": 13 }, { "key": "43", "value": 12 }, { "key": "35", "value": 11 }, { "key": "23", "value": 10 }, { "key": "39", "value": 10 }, { "key": "38", "value": 10 }, { "key": "34", "value": 10 }, { "key": "33", "value": 10 }, { "key": "40", "value": 10 }, { "key": "41", "value": 10 }, { "key": "47", "value": 9 }, { "key": "37", "value": 9 }, { "key": "21", "value": 8 }, { "key": "42", "value": 8 }, { "key": "62", "value": 7 }, { "key": "49", "value": 6 }, { "key": "54", "value": 6 }, { "key": "31", "value": 6 }, { "key": "60", "value": 6 }, { "key": "56", "value": 5 }, { "key": "59", "value": 5 }, { "key": "44", "value": 5 }, { "key": "36", "value": 5 }, { "key": "27", "value": 5 }, { "key": "74", "value": 4 }, { "key": "82", "value": 4 }, { "key": "52", "value": 4 }, { "key": "50", "value": 4 }, { "key": "98", "value": 3 }, { "key": "68", "value": 3 }, { "key": "61", "value": 3 }, { "key": "58", "value": 3 }, { "key": "105", "value": 3 }, { "key": "51", "value": 3 }, { "key": "48", "value": 3 }, { "key": "86", "value": 3 }, { "key": "45", "value": 3 }, { "key": "101", "value": 3 }, { "key": "87", "value": 2 }, { "key": "70", "value": 2 }, { "key": "64", "value": 2 }, { "key": "76", "value": 2 }, { "key": "83", "value": 2 }, { "key": "57", "value": 2 }, { "key": "134", "value": 2 }, { "key": "78", "value": 2 }, { "key": "173", "value": 2 }, { "key": "84", "value": 2 }, { "key": "75", "value": 1 }, { "key": "96", "value": 1 }, { "key": "97", "value": 1 }, { "key": "122", "value": 1 }, { "key": "108", "value": 1 }, { "key": "109", "value": 1 }, { "key": "119", "value": 1 }, { "key": "127", "value": 1 }, { "key": "55", "value": 1 }, { "key": "147", "value": 1 }, { "key": "53", "value": 1 }, { "key": "152", "value": 1 }, { "key": "166", "value": 1 }, { "key": "175", "value": 1 }, { "key": "192", "value": 1 }, { "key": "196", "value": 1 }, { "key": "229", "value": 1 }, { "key": "232", "value": 1 }, { "key": "263", "value": 1 } ], "os_status": [ { "key": "Deceased", "value": 596 }, { "key": "Living", "value": 505 }, { "key": " ", "value": 5 }, { "key": "Ltf", "value": 1 } ], "race": [ { "key": "European (non-Finnish)", "value": 604 }, { "key": "African", "value": 61 }, { "key": "Latino", "value": 35 }, { "key": "Other", "value": 19 }, { "key": "East Asian", "value": 1 } ], "tumor_status": [ { "key": "Disease Free", "value": 100 }, { "key": "Recurred", "value": 56 } ], "dfs_months": [ { "key": "19", "value": 13 }, { "key": "13", "value": 12 }, { "key": "15", "value": 9 }, { "key": "6", "value": 8 }, { "key": "3", "value": 7 }, { "key": "46", "value": 6 }, { "key": "4", "value": 5 }, { "key": "40", "value": 5 }, { "key": "43", "value": 5 }, { "key": "12", "value": 4 }, { "key": "9", "value": 4 }, { "key": "10", "value": 4 }, { "key": "0", "value": 4 }, { "key": "2", "value": 4 }, { "key": "32", "value": 3 }, { "key": "34", "value": 3 }, { "key": "1", "value": 3 }, { "key": "29", "value": 3 }, { "key": "48", "value": 3 }, { "key": "7", "value": 3 }, { "key": "74", "value": 3 }, { "key": "98", "value": 3 }, { "key": "101", "value": 3 }, { "key": "14", "value": 3 }, { "key": "28", "value": 3 }, { "key": "11", "value": 3 }, { "key": "105", "value": 3 }, { "key": "24", "value": 3 }, { "key": "23", "value": 2 }, { "key": "52", "value": 2 }, { "key": "5", "value": 2 }, { "key": "26", "value": 2 }, { "key": "70", "value": 2 }, { "key": "17", "value": 2 }, { "key": "30", "value": 2 }, { "key": "173", "value": 2 }, { "key": "78", "value": 2 }, { "key": "82", "value": 2 }, { "key": "39", "value": 2 }, { "key": "37", "value": 2 }, { "key": "85", "value": 1 }, { "key": "134", "value": 1 }, { "key": "62", "value": 1 }, { "key": "16", "value": 1 }, { "key": "61", "value": 1 }, { "key": "56", "value": 1 }, { "key": "54", "value": 1 }, { "key": "47", "value": 1 }, { "key": "44", "value": 1 }, { "key": "18", "value": 1 }, { "key": "22", "value": 1 }, { "key": "36", "value": 1 }, { "key": "33", "value": 1 }, { "key": "27", "value": 1 } ], "path_t_stage": [ { "key": "T3", "value": 40 }, { "key": "T2", "value": 24 }, { "key": "T1", "value": 11 }, { "key": "T4A", "value": 5 }, { "key": "T4", "value": 4 }, { "key": "pT3", "value": 2 }, { "key": "T2A", "value": 1 }, { "key": "T2B", "value": 1 }, { "key": "T2b", "value": 1 }, { "key": "T3/T4", "value": 1 }, { "key": "T4b", "value": 1 }, { "key": "pT4", "value": 1 } ], "pfs_status": [ { "key": "No", "value": 75 }, { "key": "Yes", "value": 73 } ], "radiation_therapy": [ { "key": "No", "value": 64 }, { "key": "Yes", "value": 33 } ], "path_n_stage": [ { "key": "N0", "value": 30 }, { "key": "N1", "value": 25 }, { "key": "N2", "value": 6 }, { "key": "N3", "value": 6 }, { "key": "N1A", "value": 4 }, { "key": "N0 (I-)", "value": 3 }, { "key": "N1B", "value": 2 }, { "key": "N2A", "value": 2 }, { "key": "N2B", "value": 2 }, { "key": "NX", "value": 2 }, { "key": "N2C", "value": 1 }, { "key": "N3A", "value": 1 }, { "key": "N3B", "value": 1 }, { "key": "N3a", "value": 1 }, { "key": "Nx", "value": 1 } ], "path_m_stage": [ { "key": "M0", "value": 67 }, { "key": "M1", "value": 5 }, { "key": "MX", "value": 4 }, { "key": "CM0 (I+)", "value": 2 } ], "new_tumor_event_after_initial_treatment": [ { "key": "No", "value": 55 }, { "key": "NO", "value": 23 }, { "key": "Yes", "value": 22 }, { "key": "YES", "value": 7 } ], "ajcc_pathologic_tumor_stage": [ { "key": "Stage IIA", "value": 12 }, { "key": "STAGE IIB", "value": 12 }, { "key": "STAGE II", "value": 10 }, { "key": "Stage IIB", "value": 10 }, { "key": "STAGE IIA", "value": 8 }, { "key": "Stage I", "value": 7 }, { "key": "STAGE IIIA", "value": 6 }, { "key": "STAGE IIIB", "value": 6 }, { "key": "STAGE I", "value": 5 }, { "key": "Stage IIIA", "value": 5 }, { "key": "STAGE III", "value": 5 }, { "key": "STAGE IIIC", "value": 5 }, { "key": "Stage III", "value": 4 }, { "key": "IIB", "value": 4 }, { "key": "Stage II", "value": 4 }, { "key": "Stage IIIC", "value": 3 }, { "key": "Stage IVA", "value": 3 }, { "key": "STAGE IV", "value": 3 }, { "key": "STAGE IVA", "value": 2 }, { "key": "STAGE IB", "value": 2 }, { "key": "IV", "value": 2 }, { "key": "Stage IIIB", "value": 2 }, { "key": "Stage IB", "value": 1 }, { "key": "STAGE IA", "value": 1 }, { "key": "IIA", "value": 1 }, { "key": "Stage IV", "value": 1 }, { "key": "IB", "value": 1 } ], "dss_status": [ { "key": "0:Alive Or Dead Tumor Free", "value": 79 }, { "key": "1:Dead With Tumor", "value": 23 }, { "key": "0", "value": 18 }, { "key": "1", "value": 3 }, { 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