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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":"116"}],"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":14304,"an_asj_male":5174,"an_eas_male":9062,"an_fin_male":11262,"an_nfe_male":63490,"an_oth_male":3206,"an_sas_male":23054,"an_afr_female":10058,"an_amr_female":20222,"an_asj_female":4898,"an_eas_female":9320,"an_fin_female":10354,"an_nfe_female":50030,"an_oth_female":2916,"an_sas_female":7530,"an_male":135726,"an_female":115328,"age_hist_het_65_70":2,"age_hist_het_70_75":1,"variant_type":"multi-snv","main_data":"ƒ = 0.0000159"}],"gnomad_exomes_coverage":[{"version":"2.1","coverage_mean":[71.68800354003906],"coverage_median":[100.0],"coverage_20_frequency":[0.9750968962675863]}],"gnomad_genomes_coverage":[{"version":"2.1","coverage_mean":[30.665000915527344],"coverage_median":[30.0],"coverage_20_frequency":[0.9259468367564928]}],"dann_snvs":[{"version":"2014","dann_score":0.9983520004882962}],"ncbi_clinvar2":[{"version":"07-Aug-2026","review_status":"reviewed by expert panel","review_stars":3,"variation_id":12366,"num_submitters":42,"pub_med_references":[1447251,1565144,1631137,2046748,7732013,8423216,9242456,9399838,10864200,11782540,12672316,14743206,15390294,15607980,15607981,15951970,16401470,16818505,17540308,17606709,17636407,18511570,19454241,20128691,20407015,20516128,20693561,21343334,21484931,21519010,21552135,21761402,22186996,22811390,22915647,23161690,23246812,24677579,25584008,25787918,25952993,26014290,26205489,26230955,26332594,26585234,26681312,27374712,27463065,27680515,27895058,27959731,28453743,28873162,29324801,29489754,30327374,30816478,31882575,33300245,33372952],"clinical_significance":["Pathogenic"],"last_evaluation":"20260715","origin":null,"accessions":[{"variant_id":10190170075771200004,"submissions":[{"submitter_date":20250819,"submission_description":[],"review_description":"Pathogenic","submitter_name":"Revvity Omics, Revvity","review_date":20250617,"method":"clinical testing","origin":"germline","diseases":[{"names":["Not Provided"]}],"date_updated":20250906,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV006321916"},{"submitter_date":20250304,"submission_description":[],"review_description":"Pathogenic","submitter_name":"Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital","review_date":20250304,"method":"clinical testing","origin":"germline","diseases":[{"names":["Not Provided"]}],"date_updated":20250311,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV004026686"},{"submitter_date":20220525,"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)"],"review_description":"Pathogenic","submitter_name":"GeneDx","review_date":20220429,"method":"clinical testing","origin":"germline","diseases":[{"names":["Not Provided"]}],"date_updated":20230304,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV000149647"},{"submitter_date":20210617,"submission_description":[],"review_description":"Pathogenic","submitter_name":"Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen","review_date":20210617,"method":"clinical testing","finding":[{"symbols":{"hp":"HP:0003002"},"normalized_phenotype":["Breast Carcinoma"]}],"origin":"germline","diseases":[{"names":["Not Provided"]}],"date_updated":20250413,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV001762058"},{"submitter_date":20220104,"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."],"review_description":"Pathogenic","submitter_name":"ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories","review_date":20210318,"origin":"germline","method":"clinical testing","finding":[{"symbols":{"medgen":"CN235283"}}],"date_updated":20220108,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV000605425"},{"submitter_date":20220125,"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)."],"review_description":"Pathogenic","submitter_name":"Genetic Services Laboratory, University of Chicago","review_date":20190403,"method":"clinical testing","origin":"germline","diseases":[{"names":["Not Provided"]}],"date_updated":20220129,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV002072052"},{"submitter_date":20170801,"submission_description":[],"review_description":"Pathogenic","submitter_name":"Quest Diagnostics Nichols Institute San Juan Capistrano","review_date":20170426,"method":"clinical testing","origin":"germline","diseases":[{"names":["Not Provided"]}],"date_updated":20220101,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV000602280"},{"submitter_name":"Mayo Clinic Laboratories, Mayo Clinic","submitter_date":20171031,"submission_description":[],"review_description":"Pathogenic","method":"clinical testing","origin":"unknown","diseases":[{"names":["Not Provided"]}],"date_updated":20180219,"clinical_significance":["Pathogenic"],"review_status":"no assertion criteria provided","accession_id":"SCV000692068"}],"submission_description":[],"review_date":20250617,"diseases":[{"symbols":{"medgen":"C3661900"},"names":["Not Provided","None Provided"]}],"date_created":20161028,"variation_id":12366,"clinical_significance":["Pathogenic"],"review_description":"Pathogenic","allele_id":27405,"title":"NM_000546.6(TP53):c.818G>A (p.Arg273His) AND not provided","accession_id":"RCV000254693"},{"variant_id":10190170075771200004,"submissions":[{"submitter_date":20241114,"submission_description":[],"review_description":"Pathogenic","submitter_name":"Clinical Genetics and Genomics, Karolinska University Hospital","review_date":20241001,"method":"clinical testing","origin":"germline","diseases":[{"names":["Tp53-Related Disorder"]}],"date_updated":20241207,"clinical_significance":["Pathogenic"],"review_status":"no assertion criteria provided","accession_id":"SCV005419164"}],"submission_description":[],"review_date":20241001,"diseases":[{"names":["Tp53-Related Disorder","Tp53-Related Condition"]}],"date_created":20241207,"variation_id":12366,"clinical_significance":["Pathogenic"],"review_description":"Pathogenic","allele_id":27405,"title":"NM_000546.6(TP53):c.818G>A (p.Arg273His) AND TP53-related disorder","accession_id":"RCV004797590"},{"variant_id":10190170075771200004,"submissions":[{"submitter_date":20241231,"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). In addition, 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). To date, the p.R273H mutation has been detected in numerous individuals/families satisfying classic criteria for LFS (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 variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation."],"review_description":"Pathogenic","submitter_name":"Ambry Genetics","review_date":20240829,"method":"clinical testing","origin":"germline","diseases":[{"symbols":{"medgen":"C0027672"}}],"date_updated":20250113,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV000186052"},{"submitter_date":20250429,"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."],"review_description":"Pathogenic","submitter_name":"Color Diagnostics, LLC DBA Color Health","review_date":20240416,"method":"clinical testing","origin":"germline","diseases":[{"symbols":{"medgen":"C0027672"}}],"date_updated":20250503,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV001735236"},{"submitter_date":20200306,"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)"],"review_description":"Likely pathogenic","submitter_name":"GeneKor MSA","review_date":20200101,"method":"clinical testing","origin":"germline","diseases":[{"symbols":{"medgen":"C0027672"},"names":["Hereditary Cancer-Predisposing Syndrome"]}],"date_updated":20200504,"clinical_significance":["Likely pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV000821786"}],"submission_description":[],"review_date":20240829,"diseases":[{"normalized_disease":["Hereditary Neoplastic Syndrome"],"symbols":{"medgen":"C0027672","mesh":"D009386","mondo":"MONDO:0015356"},"pub_med":[25394175],"names":["Hereditary Cancer-Predisposing Syndrome","Hereditary Neoplastic Syndrome","Tumor Predisposition","Hereditary Neoplastic Syndrome","Hereditary Neoplastic Syndrome"],"keyword":"Hereditary cancer syndrome"}],"date_created":20140517,"variation_id":12366,"clinical_significance":["Pathogenic","Likely pathogenic"],"review_description":"Pathogenic/Likely pathogenic","allele_id":27405,"title":"NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Hereditary cancer-predisposing syndrome","accession_id":"RCV000115738"},{"variant_id":10190170075771200004,"submissions":[{"submitter_date":20260206,"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). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). This variant disrupts the DNA binding domain which is critical for DNA binding activity (PMID: 26205489). While functional studies have not been performed to directly test the effect of this variant on TP53 protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic."],"review_description":"Pathogenic","submitter_name":"Labcorp Genetics (formerly Invitae), Labcorp","review_date":20260113,"method":"clinical testing","origin":"germline","diseases":[{"symbols":{"medgen":"C0085390"}}],"date_updated":20260215,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV000545317"},{"submitter_date":20250122,"submission_description":["The following ACMG criteria was used: PS4_VS, PS2, PM2_SUP, PS3, PP4_MOD, PM1, PP3"],"review_description":"Pathogenic","submitter_name":"Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet","review_date":20250110,"method":"clinical testing","origin":"germline","diseases":[{"symbols":{"medgen":"C0085390"}}],"date_updated":20250201,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV005685072"},{"submitter_date":20240808,"submission_description":["The NM_000546.6: c.818G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 273 (p.R273H). This variant has been reported in numerous unrelated probands meeting Classic LFS and Revised Chompret criteria. Based on this evidence, this variant scores 8 total points meeting the TP53 VCEP phenotype scoring criteria of ≥ 8 points. (PS4_Very Strong; PMIDs, 16401470, 15390294, 9242456, 10864200, 1565144, 7732013; SCV000186052.8). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with an LFS-associated cancer totaling 4 phenotype points (PS2; PMID: 1267231). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, SCV000186052.8). This variant has an allele frequency of 0.00001186 (14/1179946 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant resides within a codon (NM_00546.4: 273) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1; PMID: 8023157 ). Computational predictor scores (BayesDel = 0.52; Align GVGD = Class 25) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Very Strong, PS2, PM2_Supporting, PS3, PP4_Moderate, PM1, PP3. (Bayesian Points: 22; VCEP specifications version 2.0; 7/24/2024)."],"review_description":"Pathogenic","submitter_name":"ClinGen TP53 Variant Curation Expert Panel, ClinGen","review_date":20240805,"method":"curation","origin":"germline","diseases":[{"symbols":{"mondo":"MONDO:0018875"}}],"date_updated":20240818,"clinical_significance":["Pathogenic"],"review_status":"reviewed by expert panel","accession_id":"SCV001142550"},{"submitter_date":20240709,"submission_description":["Variant summary: TP53 c.818G>A (p.Arg273His) results in a non-conservative amino acid change located in the p53, DNA-binding domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251054 control chromosomes. c.818G>A has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome (Bougeard_2015, Varley_1997, Wasserman_2015). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.817C>T, p.Arg273Cys), supporting the critical relevance of codon 273 to TP53 protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in abolishing TP53 binding (Wasserman_2015) and functional inactiviation (Lang_2004). The following publications have been ascertained in the context of this evaluation (PMID: 25584008, 26014290, 9242456, 15607981). ClinVar contains an entry for this variant (Variation ID: 12366). Based on the evidence outlined above, the variant was classified as pathogenic."],"review_description":"Pathogenic","submitter_name":"Women's Health and Genetics/Laboratory Corporation of America, LabCorp","review_date":20240418,"method":"clinical testing","origin":"germline","diseases":[{"symbols":{"medgen":"C0085390"}}],"date_updated":20240715,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV000697450"},{"submitter_date":20250710,"submission_description":[],"review_description":"Pathogenic","submitter_name":"Molecular Pathology, Peter Maccallum Cancer Centre","review_date":20240327,"method":"clinical testing","origin":"germline","diseases":[{"symbols":{"mondo":"MONDO:0018875"}}],"date_updated":20250713,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV006277773"},{"submitter_date":20240416,"submission_description":["The c.818G>A (p.Arg273His) variant of the TP53 gene replaces arginine with histidine at codon 273 of the TP53 protein. This variant has been reported in at least 2 probands meeting classic Li-Fraumeni syndrome criteria and 4 probands meeting Chompret criteria (PMID: 16401470, 15390294, 9242456, 10864200, 1565144, 7732013). Additionally, it has been observed as a de novo variant in a proband with breast cancer at age 29 (PMID: 12672316). This variant is within a codon that is an established mutational hotspot in the TP53 gene (PMID: 2046748). Functional studies have shown that the variant results in non-functional of the protein (PMID: 12826609) and evidence of a dominant negative effect and loss of function (PMID: 30224644). This variant has been identified in 4/251054 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (a BayesDel score > 0.16 and Align-GVGD is C25). Based on the supporting evidence, the c.818G>A (p.Arg273His) variant in TP53 is interpreted as pathogenic."],"review_description":"Pathogenic","submitter_name":"All of Us Research Program, National Institutes of Health","review_date":20230428,"method":"clinical testing","origin":"germline","diseases":[{"symbols":{"mondo":"MONDO:0018875"}}],"date_updated":20240420,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV004823764"},{"submitter_date":20260212,"submission_description":["This variant has been reported to occur de novo in an affected individual in the literature with parental identity confirmed (ACMG/AMP: PS2; PMID:12672316). Well-established functional studies have demonstrated this variant to have a damaging effect on protein function or splicing (ACMG/AMP: PS3; PMIDs:12826609, 30224644). This variant has been reported at an elevated frequency in affected individuals/in multiple affected individuals in the literature (ACMG/AMP: PS4; PMIDs:1565144, 10864200, 7732013, 15390294, 16401470, 9242456, 1447251). This variant is located in a mutational hot spot and/or critical and well-established functional domain (ACMG/AMP: PM1). This variant is predicted to alter protein function or structure, or disrupt splicing by multiple in silico tools (ACMG/AMP: PP3)."],"review_description":"Pathogenic","submitter_name":"Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital","review_date":20230315,"method":"clinical testing","origin":"germline","diseases":[{"symbols":{"mondo":"MONDO:0018875"}}],"date_updated":20260215,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV007449409"},{"submitter_date":20240419,"submission_description":["The p.Arg273His variant in TP53 has been reported in at least 6 individuals with Li-Fraumeni syndrome and as a de novo occurence in an individual with breast cancer (selected publications Wong 2006 PMID: 16401470, Khayat 2004 PMID: 15390294, Varley 1997 PMID: 9242456, Chompret 2000 PMID: 10864200, Malkin 1992 PMID: 1565144, Flaman 1995 PMID: 7732013, Lalloo 2003 PMID: 12672316) and it was classified as pathogenic on August 28, 2019 by the ClinGen-approved ClinGen TP53 Variant Curation Expert Panel (Variation ID 12366). It has also been identified in 2/68014 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is within a codon that is an established hotspot in the TP53 gene (Levine 1991 PMID: 2046748). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro transactivation assays show a low functioning allele and there is evidence of a dominant negative effect and loss of function (Kato 2003 PMID: 12826609, Giacomelli 2018 PMID: 30224644). In summary, the p.Arg273His meets criteria to be classified as pathogenic for autosomal dominant Li-Fraumeni syndrome. ACMG/AMP criteria applied: PM1, PP3, PS3, PS4, PS2, PM2_Supporting."],"review_description":"Pathogenic","submitter_name":"Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine","review_date":20221103,"method":"clinical testing","origin":"germline","diseases":[{"symbols":{"orphanet":"ORPHA524"}}],"date_updated":20240420,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV004848862"},{"submitter_date":20180820,"submission_description":[],"review_description":"Pathogenic","submitter_name":"Mendelics","review_date":20180702,"method":"clinical testing","origin":"unknown","diseases":[{"normalized_disease":["Li-Fraumeni Syndrome"],"symbols":{"medgen":"C0085390"},"names":["Li-Fraumeni Syndrome"]}],"date_updated":20221211,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV000839110"},{"submitter_name":"CHARM Consortium","submitter_date":20260507,"submission_description":[],"review_description":"Pathogenic","diseases":[{"symbols":{"mondo":"MONDO:0018875"}}],"date_updated":20260614,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV007602357"}],"submission_description":[],"review_date":20240805,"diseases":[{"normalized_disease":["Li-Fraumeni Syndrome"],"symbols":{"omim":"151623","medgen":"C0085390","mondo":"MONDO:0018875"},"pub_med":[17392385,24493721,26389210,26389258],"names":["Li-Fraumeni Syndrome","Sarcoma Family Syndrome  Li  Fraumeni"]}],"date_created":20170417,"variation_id":12366,"clinical_significance":["Pathogenic"],"review_description":"Pathogenic","allele_id":27405,"title":"NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Li-Fraumeni syndrome","accession_id":"RCV000463420"},{"pub_med_references":[1565144,8423216],"variant_id":10190170075771200004,"submissions":[{"submitter_date":20241115,"submission_description":["The TP53 c.818G>A (p.Arg273His) missense change a maximum founder subpopulation frequency of 0.01% and a maximum non-founder subpopulation frequency of 0.003% in gnomAD v2.1.1 (http://gnomad.broadinstitute.org). This variant has been reported in individuals with LFS-associated cancers (PMID: 10645809, 10864200, 16401470, 22851211, 25787918, internal data). Computational evidence supports a deleterious effect of this variant on protein function. Transactivation assays show a low functioning allele according to Kato et al., and evidence of loss of function and a dominant negative effect according to Giacomelli et al. (PMID: 12826609, 30224644). This variant is a somatic hotspot variant in tumors according to the Cancer Hotspots database (cancerhotspots.org). In summary, this variant meets criteria to be classified as pathogenic."],"review_description":"Pathogenic","submitter_name":"St. Jude Molecular Pathology, St. Jude Children's Research Hospital","review_date":20240522,"method":"clinical testing","origin":"germline","diseases":[{"symbols":{"omim":"151623"}}],"date_updated":20241124,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV005402346"},{"submitter_date":20250526,"submission_description":["The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: The variant 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: 0.97). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000012366 /PMID: 1565144) and different missense changes at the same codon (p.Arg273Cys, p.Arg273Gly, p.Arg273Leu, p.Arg273Pro, p.Arg273Ser / ClinVar ID: VCV000043594, VCV000231060, VCV000376655, VCV000376656, VCV000634682 /PMID: 10864200, 11180592, 8164043, 8425176, 8479749) have been previously reported as pathogenic/likely pathogenic with strong evidence. 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). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline."],"review_description":"Pathogenic","submitter_name":"3billion","review_date":20230720,"method":"clinical testing","origin":"germline","diseases":[{"symbols":{"omim":"151623"}}],"date_updated":20250629,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV002572762"},{"submitter_date":20231023,"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]."],"review_description":"Pathogenic","submitter_name":"Myriad Genetics, Inc.","review_date":20230511,"method":"clinical testing","origin":"unknown","diseases":[{"symbols":{"omim":"151623"}}],"date_updated":20231028,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV004043518"},{"submitter_date":20211221,"submission_description":[],"review_description":"Pathogenic","submitter_name":"CENTOGENE GmbH and LLC - Guiding Precision Medicine","review_date":20211123,"method":"clinical testing","origin":"germline","diseases":[{"symbols":{"omim":"151623"}}],"date_updated":20220115,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV002059231"},{"submitter_date":20221205,"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."],"review_description":"Pathogenic","submitter_name":"New York Genome Center","review_date":20210910,"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"]}],"origin":"germline","diseases":[{"symbols":{"omim":"151623"}}],"date_updated":20221217,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV002764339"},{"submitter_date":20201216,"submission_description":[],"review_description":"Pathogenic","submitter_name":"Department of Pediatrics, Memorial Sloan Kettering Cancer Center","review_date":20201215,"method":"research","origin":"germline","diseases":[{"symbols":{"omim":"151623"}}],"date_updated":20210619,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV001478190"},{"submitter_date":20250625,"submission_description":["This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com."],"review_description":"Likely pathogenic","submitter_name":"Counsyl","review_date":20170222,"method":"clinical testing","origin":"unknown","diseases":[{"symbols":{"omim":"151623"}}],"date_updated":20250629,"clinical_significance":["Likely pathogenic"],"review_status":"no assertion criteria provided","accession_id":"SCV000677727"},{"submitter_date":20140808,"submission_description":[],"review_description":"Pathogenic","submitter_name":"Pathway Genomics","review_date":20140724,"method":"clinical testing","origin":"germline","diseases":[{"normalized_disease":["Li-Fraumeni Syndrome"],"symbols":{"omim":"151623"},"names":["Li-Fraumeni Syndrome"]}],"date_updated":20141019,"clinical_significance":["Pathogenic"],"review_status":"no assertion criteria provided","accession_id":"SCV000190004"},{"pub_med_references":[1565144,8423216],"submitter_date":20130409,"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."],"review_description":"Pathogenic","submitter_name":"OMIM","review_date":19930101,"method":"literature only","origin":"germline","diseases":[{"normalized_disease":["Li-Fraumeni Syndrome"],"names":["Li-Fraumeni Syndrome"]}],"date_updated":20130408,"clinical_significance":["Pathogenic"],"review_status":"no assertion criteria provided","accession_id":"SCV000033410"},{"submitter_name":"Genesis Genomics","submitter_date":20260411,"submission_description":[],"review_description":"Pathogenic","method":"clinical testing","finding":[{"names":["Breast Cancer"]}],"origin":"germline","diseases":[{"symbols":{"omim":"151623"}}],"date_updated":20260503,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV007580123"}],"submission_description":[],"review_date":20240522,"diseases":[{"normalized_disease":["Li-Fraumeni Syndrome"],"symbols":{"orphanet":"524","omim":"151623","medgen":"C1835398","gene":"553989"},"pub_med":[17392385,20065170,12692171,15604628,23788249,24493721,25394175,25356965,26389258,26324357],"names":["Li-Fraumeni Syndrome"]}],"date_created":20130404,"variation_id":12366,"clinical_significance":["Pathogenic"],"review_description":"Pathogenic","allele_id":27405,"title":"NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Li-Fraumeni syndrome 1","accession_id":"RCV000013163"},{"variant_id":10190170075771200004,"submissions":[{"submitter_date":20241220,"submission_description":[],"review_description":"Pathogenic","submitter_name":"Fulgent Genetics, Fulgent Genetics","review_date":20240418,"method":"clinical testing","origin":"germline","diseases":[{"symbols":{"omim":"114480"}},{"symbols":{"omim":"114500"}},{"symbols":{"omim":"114550"}},{"symbols":{"omim":"137800"}},{"symbols":{"omim":"151623"}},{"symbols":{"omim":"202300"}},{"symbols":{"omim":"259500"}},{"symbols":{"omim":"260350"}},{"symbols":{"omim":"260500"}},{"symbols":{"omim":"607107"}},{"symbols":{"omim":"614740"}},{"symbols":{"omim":"618165"}}],"date_updated":20250125,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV000611327"}],"submission_description":[],"review_date":20240418,"diseases":[{"normalized_disease":["Adrenocortical Carcinoma, Hereditary"],"symbols":{"orphanet":"1501","omim":"202300","medgen":"C1859972","mondo":"MONDO:0008734"},"names":["Adrenocortical Carcinoma, Hereditary"],"keyword":"Hereditary cancer syndrome"},{"normalized_disease":["Hereditary Breast Carcinoma"],"normalized_cancer":["Breast Cancer"],"symbols":{"omim":"114480","medgen":"C0346153","mondo":"MONDO:0016419"},"pub_med":[15604628,18163131,17508274,24366376,24366402,24432435,26389210,26389258,34242744,31429903],"names":["Hereditary Breast Carcinoma","Hereditary Breast Carcinoma","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"},"names":["Glioma Susceptibility 1","Glioma Susceptibility 1"],"keyword":"Neoplasm"},{"normalized_disease":["Bone Osteosarcoma"],"symbols":{"orphanet":"668","omim":"259500","medgen":"C0585442","mondo":"MONDO:0002629"},"names":["Bone Osteosarcoma","Bone Osteosarcoma"]},{"normalized_disease":["Li-Fraumeni Syndrome"],"symbols":{"orphanet":"524","omim":"151623","medgen":"C1835398","gene":"553989"},"pub_med":[17392385,20065170,12692171,15604628,23788249,24493721,25394175,25356965,26389258,26324357],"names":["Li-Fraumeni Syndrome"]},{"normalized_disease":["Malignant Tumor of Nasopharynx","Nasopharyngeal Carcinoma, Susceptibility to, 1"],"normalized_cancer":["Nasopharyngeal Carcinoma"],"symbols":{"orphanet":"150","omim":"607107","medgen":"C2931822","mondo":"MONDO:0015459"},"names":["Malignant Tumor of Nasopharynx","Nasopharyngeal Carcinoma, Susceptibility to, 1"],"keyword":"Hereditary cancer syndrome"},{"normalized_disease":["Choroid Plexus Papilloma"],"normalized_cancer":["Choroid Plexus Papilloma"],"symbols":{"orphanet":"251899","omim":"260500","medgen":"C0205770","mondo":"MONDO:0009837","human_phenotype_ontology":"HP:0200022"},"names":["Choroid Plexus Papilloma","Choroid Plexus Papilloma"]},{"normalized_disease":["Basal Cell Carcinoma, Susceptibility to, 7"],"symbols":{"omim":"614740","medgen":"C3553606","mondo":"MONDO:0013876"},"names":["Basal Cell Carcinoma, Susceptibility to, 7"]},{"normalized_disease":["Familial Pancreatic Carcinoma"],"symbols":{"omim":"260350","medgen":"C2931038","mondo":"MONDO:0015278"},"pub_med":[25645574],"names":["Familial Pancreatic Carcinoma"],"keyword":"Hereditary cancer syndrome"},{"normalized_disease":["Carcinoma of Liver and Intrahepatic Biliary Tract"],"normalized_cancer":["Hepatocellular Carcinoma"],"symbols":{"omim":"114550","medgen":"C2239176","mondo":"MONDO:0007256","human_phenotype_ontology":"HP:0006750"},"names":["Carcinoma of Liver and Intrahepatic Biliary Tract","Primary Carcinoma  Liver","Carcinoma of Liver and Intrahepatic Biliary Tract","Carcinoma of Liver and Intrahepatic Biliary Tract"],"keyword":"Hereditary cancer syndrome"},{"normalized_disease":["Colorectal Cancer"],"normalized_cancer":["Colorectal Cancer"],"symbols":{"omim":"114500","medgen":"C0346629","mondo":"MONDO:0005575"},"pub_med":[26389505,26389258,34043773],"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"]}],"date_created":20250125,"variation_id":12366,"clinical_significance":["Pathogenic"],"review_description":"Pathogenic","allele_id":27405,"title":"NM_000546.6(TP53):c.818G>A (p.Arg273His) AND multiple conditions","accession_id":"RCV005003353"},{"variant_id":10190170075771200004,"submissions":[{"submitter_date":20240605,"submission_description":[],"review_description":"Pathogenic","submitter_name":"Baylor Genetics","review_date":20240330,"method":"clinical testing","origin":"unknown","diseases":[{"symbols":{"omim":"202300"}}],"date_updated":20240617,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV004206253"}],"submission_description":[],"review_date":20240330,"diseases":[{"normalized_disease":["Adrenocortical Carcinoma, Hereditary"],"symbols":{"orphanet":"1501","omim":"202300","medgen":"C1859972","mondo":"MONDO:0008734"},"names":["Adrenocortical Carcinoma, Hereditary"],"keyword":"Hereditary cancer syndrome"}],"date_created":20231230,"variation_id":12366,"clinical_significance":["Pathogenic"],"review_description":"Pathogenic","allele_id":27405,"title":"NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Adrenocortical carcinoma, hereditary","accession_id":"RCV003466853"},{"variant_id":10190170075771200004,"submissions":[{"submitter_date":20240130,"submission_description":[],"review_description":"Likely pathogenic","submitter_name":"CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario","review_date":20230126,"method":"clinical testing","origin":"germline","diseases":[{"symbols":{"medgen":"CN221562"}}],"date_updated":20240204,"clinical_significance":["Likely pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV004239792"}],"submission_description":[],"review_date":20230126,"diseases":[{"symbols":{"medgen":"CN221562"},"names":["Breast / Ovarian Cancer"]}],"date_created":20240204,"variation_id":12366,"clinical_significance":["Likely pathogenic"],"review_description":"Likely pathogenic","allele_id":27405,"title":"NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Breast and/or ovarian cancer","accession_id":"RCV003492292"},{"variant_id":10190170075771200004,"submissions":[{"submitter_date":20230220,"submission_description":[],"review_description":"Pathogenic","submitter_name":"Liquid Biopsy and Cancer Interception Group, Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research","review_date":20220606,"method":"research","origin":"somatic","diseases":[{"symbols":{"mondo":"MONDO:0005061"}}],"date_updated":20230304,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV003806294"}],"submission_description":[],"review_date":20220606,"diseases":[{"normalized_disease":["Lung Adenocarcinoma","Lung Cancer"],"normalized_cancer":["Lung Adenocarcinoma"],"symbols":{"medgen":"C0152013","mesh":"D000077192","mondo":"MONDO:0005061","human_phenotype_ontology":"HP:0030078"},"pub_med":[23562183,25311215,24627688,29355391,29398453],"names":["Lung Adenocarcinoma","Lung Adenocarcinoma","Lung Cancer"]}],"date_created":20170308,"variation_id":12366,"clinical_significance":["Pathogenic"],"review_description":"Pathogenic","allele_id":27405,"title":"NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Lung adenocarcinoma","accession_id":"RCV000431361"},{"variant_id":10190170075771200004,"submissions":[{"submitter_date":20221201,"submission_description":[],"review_description":"Pathogenic","submitter_name":"Laboratory for Genotyping Development, RIKEN","review_date":20210701,"method":"research","origin":"germline","diseases":[{"symbols":{"mesh":"D013274"}}],"date_updated":20230415,"clinical_significance":["Pathogenic"],"review_status":"no assertion criteria provided","accession_id":"SCV002758479"}],"submission_description":[],"review_date":20210701,"diseases":[{"normalized_disease":["Gastric Cancer"],"normalized_cancer":["Esophageal/Stomach Cancer"],"symbols":{"medgen":"C0024623","omim":"613659","mesh":"D013274","mondo":"MONDO:0001056","human_phenotype_ontology":"HP:0012126"},"names":["Gastric Cancer","Gastric Cancer","Gastric Cancer"]}],"date_created":20230415,"variation_id":12366,"clinical_significance":["Pathogenic"],"review_description":"Pathogenic","allele_id":27405,"title":"NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Gastric cancer","accession_id":"RCV003162246"},{"variant_id":10190170075771200004,"submissions":[{"submitter_date":20210519,"submission_description":[],"review_description":"Pathogenic","submitter_name":"University Health Network, Princess Margaret Cancer Centre","review_date":20210319,"method":"clinical testing","origin":"somatic","diseases":[{"symbols":{"omim":"167000"}}],"date_updated":20210626,"clinical_significance":["Pathogenic"],"review_status":"no assertion criteria provided","accession_id":"SCV001738490"},{"submitter_date":20190222,"submission_description":[],"review_description":"Likely pathogenic","submitter_name":"German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne","review_date":20181201,"diseases":[{"symbols":{"mesh":"D010051"}}],"date_updated":20190617,"clinical_significance":["Likely pathogenic"],"review_status":"no assertion criteria provided","accession_id":"SCV000923913"}],"submission_description":[],"review_date":20210319,"diseases":[{"normalized_disease":["Ovarian Neoplasm"],"normalized_cancer":["Ovarian/Fallopian Tube Cancer"],"symbols":{"medgen":"C0919267","mesh":"D010051","mondo":"MONDO:0021068","human_phenotype_ontology":"HP:0100615"},"pub_med":[19042984,22964825,23188549,33410258,29450531],"names":["Ovarian Neoplasm","Ovarian Neoplasm","Ovarian Neoplasm","Ovarian Neoplasms"]}],"date_created":20190617,"variation_id":12366,"clinical_significance":["Pathogenic","Likely pathogenic"],"review_description":"Pathogenic/Likely pathogenic","allele_id":27405,"title":"NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Ovarian neoplasm","accession_id":"RCV000785345"},{"variant_id":10190170075771200004,"submissions":[{"submitter_date":20210519,"submission_description":[],"review_description":"Pathogenic","submitter_name":"University Health Network, Princess Margaret Cancer Centre","review_date":20210319,"origin":"somatic","method":"clinical testing","date_updated":20210626,"clinical_significance":["Pathogenic"],"review_status":"no assertion criteria provided","accession_id":"SCV001738487"}],"submission_description":[],"review_date":20210319,"diseases":[{"normalized_disease":["Plasma Cell Myeloma"],"normalized_cancer":["Plasma Cell Myeloma"],"symbols":{"orphanet":"85443","medgen":"C0026764","omim":"254500","mesh":"D009101","mondo":"MONDO:0009693","human_phenotype_ontology":"HP:0006775"},"names":["Plasma Cell Myeloma","Plasma Cell Myeloma","Multiple Myeloma, Somatic"],"keyword":"Hereditary cancer syndrome"},{"normalized_disease":["Colorectal Cancer"],"normalized_cancer":["Colorectal Cancer"],"symbols":{"omim":"114500","medgen":"C0346629","mondo":"MONDO:0005575"},"pub_med":[26389505,26389258,34043773],"names":["Colorectal Cancer","Colorectal Cancer","Colorectal Cancer"]}],"date_created":20210626,"variation_id":12366,"clinical_significance":["Pathogenic"],"review_description":"Pathogenic","allele_id":27405,"title":"NM_000546.6(TP53):c.818G>A (p.Arg273His) AND multiple conditions","accession_id":"RCV001527470"},{"variant_id":10190170075771200004,"submissions":[{"submitter_date":20210519,"submission_description":[],"review_description":"Pathogenic","submitter_name":"University Health Network, Princess Margaret Cancer Centre","review_date":20210319,"method":"clinical testing","origin":"somatic","diseases":[{"symbols":{"omim":"114480"}}],"date_updated":20210626,"clinical_significance":["Pathogenic"],"review_status":"no assertion criteria provided","accession_id":"SCV001738505"}],"submission_description":[],"review_date":20210319,"diseases":[{"normalized_disease":["Hereditary Breast Carcinoma"],"normalized_cancer":["Breast Cancer"],"symbols":{"omim":"114480","medgen":"C0346153","mondo":"MONDO:0016419"},"pub_med":[15604628,18163131,17508274,24366376,24366402,24432435,26389210,26389258,34242744,31429903],"names":["Hereditary Breast Carcinoma","Hereditary Breast Carcinoma","Hereditary Breast Carcinoma","Hereditary Breast Carcinoma"],"keyword":"Hereditary cancer syndrome","disease_mechanism":"loss of function"}],"date_created":20210626,"variation_id":12366,"clinical_significance":["Pathogenic"],"review_description":"Pathogenic","allele_id":27405,"title":"NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Familial cancer of breast","accession_id":"RCV001527484"},{"variant_id":10190170075771200004,"submissions":[{"submitter_date":20251120,"submission_description":["Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in rhabdomyosarcoma, based on the following evidence: 1) Information in the literature supports potential biologic effect of variant (PMIDs: 12826609, 15781620, 30224644). 2) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B)."],"submitter_name":"Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital","review_date":20240709,"method":"clinical testing","origin":"somatic","diseases":[{"symbols":{"mondo":"MONDO:0005212"}}],"date_updated":20251122,"clinical_significance":[],"review_status":"criteria provided, single submitter","accession_id":"SCV007105534"},{"submitter_date":20200906,"submission_description":[],"review_description":"Pathogenic","submitter_name":"Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine","review_date":20200901,"method":"provider interpretation","origin":"germline","diseases":[{"normalized_disease":["Rhabdomyosarcoma"],"normalized_cancer":["Rhabdomyosarcoma"],"names":["Rhabdomyosarcoma"]}],"date_updated":20201003,"clinical_significance":["Pathogenic"],"review_status":"no assertion criteria provided","accession_id":"SCV001434343"}],"submission_description":[],"review_date":20200901,"diseases":[{"normalized_disease":["Rhabdomyosarcoma"],"normalized_cancer":["Rhabdomyosarcoma"],"symbols":{"medgen":"C0035412","mesh":"D012208","mondo":"MONDO:0005212","human_phenotype_ontology":"HP:0002859"},"names":["Rhabdomyosarcoma","Rhabdomyosarcoma"]}],"date_created":20201003,"variation_id":12366,"clinical_significance":["Pathogenic"],"review_description":"Pathogenic","allele_id":27405,"title":"NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Rhabdomyosarcoma","accession_id":"RCV001257517"},{"pub_med_references":[1565144,8423216],"variant_id":10190170075771200004,"submissions":[{"pub_med_references":[1565144,8423216],"submitter_date":20130409,"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."],"review_description":"Pathogenic","submitter_name":"OMIM","review_date":19930101,"method":"literature only","origin":"somatic","diseases":[{"names":["Thyroid Carcinoma, Anaplastic, Somatic"]}],"date_updated":20130408,"clinical_significance":["Pathogenic"],"review_status":"no assertion criteria provided","accession_id":"SCV000033411"}],"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."],"review_date":19930101,"diseases":[{"normalized_disease":["Thyroid Gland Undifferentiated (Anaplastic) Carcinoma"],"normalized_cancer":["Anaplastic Thyroid Cancer"],"symbols":{"medgen":"C0238461","mesh":"D065646","mondo":"MONDO:0006468","human_phenotype_ontology":"HP:0011779"},"names":["Thyroid Gland Undifferentiated (Anaplastic) Carcinoma","Thyroid Gland Undifferentiated (Anaplastic) Carcinoma","Thyroid Gland Undifferentiated (Anaplastic) Carcinoma","Thyroid Carcinoma, Anaplastic, Somatic"],"keyword":"Neoplasm"}],"date_created":20130404,"variation_id":12366,"clinical_significance":["Pathogenic"],"review_description":"Pathogenic","allele_id":27405,"title":"NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Thyroid gland undifferentiated (anaplastic) carcinoma","accession_id":"RCV000013164"},{"variant_id":10190170075771200004,"submissions":[{"submitter_name":"Department of Pathology and Laboratory Medicine, Sinai Health System","submitter_date":20210331,"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."],"review_description":"Pathogenic","method":"clinical testing","origin":"unknown","diseases":[{"symbols":{"mondo":"MONDO:0007254"}}],"date_updated":20210413,"clinical_significance":["Pathogenic"],"review_status":"no assertion criteria provided","accession_id":"SCV001554107"}],"submission_description":[],"finding":[{"symbols":{"medgen":"C0006142","mondo":"MONDO:0007254"},"names":["Breast Cancer","Breast Cancer","Breast Cancer"],"disease_mechanism":"loss of function"}],"date_created":20210413,"variation_id":12366,"clinical_significance":["Pathogenic"],"review_description":"Pathogenic","allele_id":27405,"title":"NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Malignant tumor of breast","accession_id":"RCV001358389"},{"variant_id":10190170075771200004,"submissions":[{"submitter_date":20250304,"submission_description":[],"submitter_name":"Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital","review_date":20250304,"method":"clinical testing","origin":"somatic","diseases":[{"symbols":{"medgen":"C0027651"}}],"date_updated":20250311,"clinical_significance":[],"review_status":"criteria provided, single submitter","accession_id":"SCV005094393"}],"submission_description":[],"diseases":[{"normalized_disease":["Neoplasm"],"normalized_cancer":["Cancer (generic)"],"symbols":{"medgen":"C0027651","mesh":"D009369","mondo":"MONDO:0005070","human_phenotype_ontology":"HP:0006741"},"pub_med":[22918138,23619274,34131312],"names":["Neoplasm","Neoplasms","Neoplasm","Neoplasm"],"keyword":"neoplasm"}],"date_created":20170308,"variation_id":12366,"clinical_significance":[],"allele_id":27405,"title":"NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Neoplasm","accession_id":"RCV000441169"},{"variant_id":10190170075771200004,"submissions":[{"submitter_name":"Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo","submitter_date":20201208,"submission_description":[],"review_description":"Pathogenic","method":"case-control","origin":"somatic","diseases":[{"symbols":{"omim":"275355"}}],"date_updated":20250413,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV001450494"}],"submission_description":[],"diseases":[{"normalized_disease":["Head and Neck Squamous Cell Carcinoma"],"normalized_cancer":["Head and Neck Squamous Cell Carcinoma"],"symbols":{"orphanet":"67037","medgen":"C1168401","omim":"275355","mesh":"D000077195","mondo":"MONDO:0010150"},"names":["Head and Neck Squamous Cell Carcinoma","Head and Neck Squamous Cell Carcinoma","Head and Neck Squamous Cell Carcinoma"],"keyword":"Hereditary cancer syndrome"}],"date_created":20170308,"variation_id":12366,"clinical_significance":["Pathogenic"],"review_description":"Pathogenic","allele_id":27405,"title":"NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Squamous cell carcinoma of the head and neck","accession_id":"RCV000422097"},{"variant_id":10190170075771200004,"submissions":[{"submitter_date":20251120,"submission_description":["Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in Ewing sarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant. 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 25010205, 25223734, 25186949, 35705560, 30927420)."],"submitter_name":"Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital","review_date":20240110,"method":"clinical testing","origin":"somatic","diseases":[{"symbols":{"mondo":"MONDO:0012817"}}],"date_updated":20251122,"clinical_significance":[],"review_status":"criteria provided, single submitter","accession_id":"SCV007104721"}],"submission_description":[],"diseases":[{"normalized_disease":["Epithelioid Sarcoma"],"normalized_cancer":["Ewing Sarcoma"],"symbols":{"orphanet":"319","omim":"612219","medgen":"C0553580","mondo":"MONDO:0012817","human_phenotype_ontology":"HP:0012254"},"names":["Epithelioid Sarcoma","Epithelioid Sarcoma","Epithelioid Sarcoma","Ewing Tumor"],"keyword":"Hereditary cancer syndrome"}],"date_created":20251122,"variation_id":12366,"clinical_significance":[],"allele_id":27405,"title":"NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Ewing sarcoma","accession_id":"RCV006253496"},{"variant_id":10190170075771200004,"submissions":[{"submitter_date":20251120,"submission_description":["Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in desmoplastic small round cell tumor, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMIDs: 12826609, 15781620, 30224644). 3) Diagnostic significance based on multiple small studies (Evidence Level C; PMIDs: 33753552, 32393201, 35705560, 35705558)."],"submitter_name":"Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital","review_date":20250305,"method":"clinical testing","origin":"somatic","diseases":[{"symbols":{"mondo":"MONDO:0019373"}}],"date_updated":20251122,"clinical_significance":[],"review_status":"criteria provided, single submitter","accession_id":"SCV007105589"}],"submission_description":[],"diseases":[{"normalized_disease":["Desmoplastic Small Round Cell Tumor"],"normalized_cancer":["Desmoplastic Small-Round-Cell Tumor"],"symbols":{"medgen":"C0281508","mondo":"MONDO:0019373"},"names":["Desmoplastic Small Round Cell Tumor"]}],"date_created":20251122,"variation_id":12366,"clinical_significance":[],"allele_id":27405,"title":"NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Desmoplastic small round cell tumor","accession_id":"RCV006253497"},{"variant_id":10190170075771200004,"submissions":[{"submitter_date":20251120,"submission_description":["Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 12826609, 15781620, 25584008, 31776133). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 28966033, 29763623, 24705251, 28912153, 25219808)."],"submitter_name":"Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital","review_date":20250702,"method":"clinical testing","origin":"somatic","diseases":[{"symbols":{"mondo":"MONDO:0858939"}}],"date_updated":20251122,"clinical_significance":[],"review_status":"criteria provided, single submitter","accession_id":"SCV007105622"}],"submission_description":[],"diseases":[{"normalized_disease":["Diffuse Pediatric- High-Grade Glioma, H3-Wildtype  Idh-Wildtype"],"normalized_cancer":["Diffuse Pediatric-Type High-Grade Glioma, H3-Wildtype and IDH-Wildtype"],"symbols":{"medgen":"C5669918","mondo":"MONDO:0858939"},"names":["Diffuse Pediatric- High-Grade Glioma, H3-Wildtype  Idh-Wildtype"]}],"date_created":20251122,"variation_id":12366,"clinical_significance":[],"allele_id":27405,"title":"NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype","accession_id":"RCV006253498"},{"variant_id":10190170075771200004,"submissions":[{"submitter_date":20251120,"submission_description":["Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse midline glioma, H3 K27M-mutant, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 12826609, 30224644). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24705251, 28966033, 22661320, 34796414, 33433639, 37524847, 39256213)."],"submitter_name":"Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital","review_date":20251031,"method":"clinical testing","origin":"somatic","diseases":[{"symbols":{"mondo":"MONDO:0957196"}}],"date_updated":20251122,"clinical_significance":[],"review_status":"criteria provided, single submitter","accession_id":"SCV007105500"}],"submission_description":[],"diseases":[{"normalized_disease":["Diffuse Midline Glioma, H3 K27M-Mutant"],"normalized_cancer":["Diffuse Midline Glioma, H3 K27-Altered"],"symbols":{"medgen":"C4289688","mondo":"MONDO:0957196"},"names":["Diffuse Midline Glioma, H3 K27M-Mutant"]}],"date_created":20251122,"variation_id":12366,"clinical_significance":[],"allele_id":27405,"title":"NM_000546.6(TP53):c.818G>A (p.Arg273His) AND Diffuse midline glioma, H3 K27M-mutant","accession_id":"RCV006253499"}],"main_data":"pathogenic **3**","names":["NM_000546.6(TP53):c.818G>A (p.Arg273His)","p.R273H:CGT>CAT"],"variant_type":"SNV"}],"iarc_tp53_germline":[{"version":"release 20","sex":[{"key":"Female","value":95},{"key":"Male","value":35}],"age_freq":[{"key":"30-40","value":8},{"key":"20-30","value":5},{"key":"40-50","value":5},{"key":"10-20","value":2},{"key":"5-10","value":2},{"key":"50-60","value":2},{"key":"60-70","value":2},{"key":"1-5","value":1}],"country":[{"key":"Usa","value":23},{"key":"France","value":17},{"key":"Canada","value":16},{"key":"India","value":13},{"key":"China","value":12},{"key":"Uk","value":11},{"key":"Germany","value":10},{"key":"Bosnia And Herzegovina","value":8},{"key":"Ireland","value":7},{"key":"Korea","value":7},{"key":"Japan","value":5},{"key":"Austria","value":3},{"key":"Europe, Nos","value":2},{"key":"Northern America, Nos","value":2},{"key":"Denmark","value":1},{"key":"The Netherlands","value":1}],"hotspot":true,"effect":"missense","pub_med_references":null,"total_samples":141,"oncotree_code":[{"key":"BREAST","value":32},{"key":"OS","value":15},{"key":"RMS","value":12},{"key":"SARCNOS","value":8},{"key":"ADNOS","value":5},{"key":"BRAIN","value":5},{"key":"NBL","value":3},{"key":"GINETES","value":3},{"key":"CPC","value":2},{"key":"GB","value":2},{"key":"KIDNEY","value":2},{"key":"AML","value":2},{"key":"TAML","value":1},{"key":"AASTR","value":1},{"key":"RCC","value":1},{"key":"PNET","value":1},{"key":"PANCREAS","value":1},{"key":"UTERUS","value":1},{"key":"NHL","value":1},{"key":"MEL","value":1},{"key":"MBL","value":1},{"key":"LMS","value":1},{"key":"LIPO","value":1},{"key":"HEMA","value":1},{"key":"FA","value":1},{"key":"BCC","value":1},{"key":"ASTR","value":1}],"cancer_name":[{"key":"Cancer, NOS","value":44},{"key":"Osteosarcoma, NOS (C40._, C41._)","value":15},{"key":"Rhabdomyosarcoma, NOS","value":12},{"key":"Sarcoma, NOS","value":8},{"key":"Infiltrating duct carcinoma, NOS (C50._)","value":7},{"key":"Adenocarcinoma, NOS","value":5},{"key":"Adrenal cortical carcinoma (C74.0)","value":5},{"key":"Neuroblastoma, NOS","value":3},{"key":"Bronchiolo-alveolar adenocarcinoma (C34._)","value":2},{"key":"Carcinoma, NOS","value":2},{"key":"Choroid plexus carcinoma (C71.5)","value":2},{"key":"Germ cell tumor, nonseminomatous (C62._)","value":2},{"key":"Glioblastoma, NOS (C71._)","value":2},{"key":"Acute leukemia, NOS","value":2},{"key":"Acute myeloid leukemia, NOS","value":2},{"key":"Serous cystadenocarcinoma, NOS (C56.9)","value":1},{"key":"Spindle cell sarcoma","value":1},{"key":"Renal cell carcinoma, NOS (C64.9)","value":1},{"key":"Primitive neuroectodermal tumor, NOS (C71._)","value":1},{"key":"Pleomorphic rhabdomyosarcoma, adult type","value":1},{"key":"Phyllodes tumor, malignant (C50._)","value":1},{"key":"Phyllodes tumor, benign (C50._)","value":1},{"key":"Papillary carcinoma, 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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":"ENST00000269305.4","transcripts":null,"variant":"R273H","variant_civic_url":"https://civicdb.org/links/variants/122","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":"Substitutes","drugs":["Doxorubicin","Methotrexate"],"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":"ENST00000269305.4","transcripts":null,"variant":"R273H","variant_civic_url":"https://civicdb.org/links/variants/122","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 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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":"NM_000546.6","possible_functional_studies":[10570149,7682763],"pub_med_references":[1394225,1565144,1699228,1868473,7682763,8423216,10570149,20385133,31882575],"disease_name":["Adenomas and Adenocarcinomas","Adenomas and Adenocarcinomas","Adenomas and Adenocarcinomas","Adenomas and Adenocarcinomas","Adenomas and Adenocarcinomas"],"annotation_id":"VAR_005995"}]}}]}],"alpha_missense":[{"version":"03-Jul-2024","main_data":"Likely Pathogenic","alpha_missense_score":0.988891262550737}],"acmg_annotation":{"version_name":"13.19.0","gene_symbol":"TP53","transcript":"NM_000546.6","transcript_reason":"MANE select","coding_impact":"missense","blosum_score":-1,"verdict":{"ACMG_rules":{"benign_score":0,"benign_subscore":"Uncertain Significance","clinical_score":5.266,"pathogenic_score":16,"pathogenic_subscore":"Pathogenic","total_score":16,"verdict":"Pathogenic"},"classifications":["PP5_Very Strong","PM1","PM5","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 Jun '26, 51 submissions of which 4 are from high confidence submitters), citing 11 articles (%%PUBMED:33372952%%, %%PUBMED:33300245%%, %%PUBMED:31882575%%, %%PUBMED:30816478%%, %%PUBMED:30327374%%, and 6 more), associated with Adrenocortical Carcinoma, Hereditary, Basal Cell Carcinoma, Susceptibility to, 7, Bone Marrow Failure Syndrome 5, and Bone Osteosarcoma.","Moderate: VarSome users have classified this variant as Pathogenic, citing %%PUBMED:33990091%%, Pathogenic, citing %%PUBMED:29026176%%, Pathogenic, citing %%PUBMED:29522266%%, Pathogenic (automatically lifted-over from chr17:7673802 C⇒T on hg38), citing %%PUBMED:30126368%% and Pathogenic (automatically lifted-over from chr17:7673802 C⇒T on hg38), citing %%PUBMED:30723117%%."],"strength":"Very Strong"},{"name":"PM1","met_criteria":true,"user_explain":["Hot-spot of length 17 amino-acids has 116 missense/in-frame variants (60 pathogenic variants, 54 uncertain variants, and 2 benign variants), which qualifies as strong pathogenic.","UniProt protein P53_HUMAN region of interest 'Interaction with DNA' has 64 missense/in-frame variants (32 pathogenic variants, 31 uncertain variants, and 1 benign variant), which qualifies as moderate pathogenic.","UniProt protein P53_HUMAN DNA-binding domain 'DNA-binding region_102-292' has 1 111 missense/in-frame variants (426 pathogenic variants, 667 uncertain variants, and 18 benign variants), which qualifies as moderate pathogenic.","UniProt protein P53_HUMAN region of interest 'Interaction with AXIN1' has 1 032 missense/in-frame variants (393 pathogenic variants, 623 uncertain variants, and 16 benign variants), which qualifies as moderate pathogenic.","UniProt protein P53_HUMAN region of interest 'Interaction with E4F1' has 233 missense/in-frame variants (89 pathogenic variants, 140 uncertain variants, and 4 benign variants), which qualifies as moderate pathogenic.","UniProt protein P53_HUMAN region of interest 'Required for interaction with ZNF385A' has 1 143 missense/in-frame variants (427 pathogenic variants, 697 uncertain variants, and 19 benign variants), which qualifies as moderate pathogenic.","UniProt protein P53_HUMAN region of interest 'Interaction with CCAR2' has 1 511 missense/in-frame variants (433 pathogenic variants, 1 007 uncertain variants, and 71 benign variants), which qualifies as supporting pathogenic.","UniProt protein P53_HUMAN region of interest 'Interaction with HIPK1' has 1 420 missense/in-frame variants (452 pathogenic variants, 900 uncertain variants, and 68 benign variants), which qualifies as supporting pathogenic.","Limiting strength to Moderate due to co-occurrence with other predictive evidence."]},{"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, 2 stars, by ClinVar (confirmed using the germline classifier).","Alternative variant ##chr17:7577120 C⇒G## (Arg273Pro) is classified Pathogenic, 2 stars, by ClinVar (confirmed using the germline classifier).","Alternative variant ##chr17:7577120 C⇒A## (Arg273Leu) is classified Pathogenic, 2 stars, by ClinVar (confirmed using the germline classifier).","5 pathogenic alternative variants identified.","Limiting strength to Moderate due to co-occurrence with other 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Alveolar Rhabdomyosarcoma, B-Cell Chronic Lymphocytic Leukemia, B-Lymphoblastic Leukemia/Lymphoma  T(9;22)(Q34.1;Q11.2), and 26 more, according to CGD, ClinGen Disease Validity, GenCC, Mondo, and gene2phenotype.","mode_of_inheritance":"AD, based on gene information from CGD, ClinGen Disease Validity, GenCC, Mondo, and gene2phenotype."}},"amp_annotation":{"version_name":"13.19.0","verdict":{"tier":"Tier I","approx_score":3.355},"classifications":[{"name":"Crtd","tier":"Tier I","user_explain":{"Tier I":["AML with Myelodysplasia-Related Changes, Acute Myeloid Leukemia, Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Essential Thrombocythemia, and 5 more, prognostic, curated, from OncoKB, citing %%PUBMED:29296692%%, %%PUBMED:28819011%%, %%PUBMED:26022239%%, %%PUBMED:25952993%%, and 20 more. 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