Submissions for variant NM_000546.6(TP53):c.814G>A (p.Val272Met)

dbSNP: rs121912657

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV001527085	SCV001737924	pathogenic	Li-Fraumeni syndrome 1	2022-03-18	reviewed by expert panel	curation	This variant has >10 observations as a somatic hotspot variant in tumors (PM1; cancerhotspots.org v(2)). 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 4 probands meeting Chompret criteria (PS4_Moderate; PMID: 25584008, 23175693, IARC, NIH). There are de novo observations in 2 probands with childhood rhabdomyosarcoma, osteosarcoma, without parental confirmation (PM6_Strong; PMID: IARC, NIH). In summary, TP53 c.814G>A (p.Val272Met) 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, PS3, PS4_Moderate, PM6_Strong.
Ambry Genetics	RCV000165304	SCV000216025	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-10	criteria provided, single submitter	clinical testing	The p.V272M pathogenic mutation (also known as c.814G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 814. The valine at codon 272 is replaced by methionine, an amino acid with highly similar properties. This alteration has been detected in a French family with features suggestive of Li-Fraumeni syndrome, a patient diagnosed with rhabdomyosarcoma at age 1 and osteosarcoma at age 2, as well as a patient diagnosed with medulloblastoma at age 3 (Bougeard G et al. J. Med. Genet. 2008 Aug;45(8):535-8; Renaux-Petel M et al. J. Med. Genet. 2017 Oct 25). This alteration was also identified in a patient with late onset adrenal cortical carcinoma (Raymond VM et al. J. Clin. Endocrinol. Metab. 2013 Jan; 98(1):E119-25). The p.V272M alteration has been reported as a somatic alteration in a variety of tumors (Marinelli M et al. Haematologica 2013 Mar; 98(3):371-5; Chiaretti S et al. Genes Chromosomes Cancer 2011 Apr; 50(4):263-74; Chang MT et al. Cancer Discov. 2018 02;8:174-183). This alteration is a well-known temperature sensitive alteration that causes abnormal protein folding and prevents DNA binding at temperatures above 37 degrees Celsius (da Costa NM et al. Cell Cycle 2012 Dec;11(24):4570-8). Functional studies have demonstrated that this alteration interferes with p53 up-regulation in response to DNA damaging agents and shows loss of transactivation capacity in yeast based assays (Barnas Cet al. Int. J. Cancer 1997 Mar;71(1):79-87). Studies conducted in human cell lines indicate this alteration has a dominant negative effect and is deficient at growth suppression (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457645	SCV000545259	pathogenic	Li-Fraumeni syndrome	2024-09-25	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 272 of the TP53 protein (p.Val272Met). 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 (PMID: 18511570, 23175693, 25584008, 29070607). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 185814). 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: 9290701, 9635828, 12826609, 16861262, 22710932). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV002243833	SCV002513657	pathogenic	not provided	2023-04-11	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: non-functional transactivation, lack of growth suppression and apoptotic activities, and a dominant-negative effect per some reporters (Ponchel et al., 1998; Kato et al., 2003; Baroni et al., 2004; Dearth et al., 2007; Giacomelli et al., 2018; Kotler et al., 2018); Identified in individuals reported to have Li-Fraumeni-related cancers (Bougeard et al., 2008; Raymond et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16322298, 7651740, 9635828, 26230955, 27121310, 21643842, 15037740, 16861262, 11429700, 10753186, 9096669, 19003964, 9290701, 14559903, 26425688, 25787918, 27101868, 27926791, 21319261, 15221786, 25584008, 11870884, 25407396, 28861920, 30720243, 30840781, 34426522, 29997966, 27311873, 31200822, Kim2019[article], 32371587, 33531134, 28243320, 32260152, 35974385, 23175693, 30914417, 18511570, 12826609, 29979965, 30224644, 29070607, 15510160, 32658383, 34544131, 34382015, 34306021, 34583722, 34544143, 32165485, 32164171)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000457645	SCV004848443	likely pathogenic	Li-Fraumeni syndrome	2020-08-10	criteria provided, single submitter	clinical testing	The p.Val272Met variant in TP53 has been reported in 3 individuals with Li-Fraumeni syndrome or adrenocortical carcinoma and one individual with rhabdomyosarcoma with a de novo mutation (Bougeard 2008 PMID: 18511570, Raymond 2013 PMID: 23175693, Wasserman 2015 PMID: 25584008, Renaux-Petel 2018 PMID: 29070607). It has also been identified in 0.0009% (1/113432) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 185814). 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 functional studies provide some evidence that this variant disrupts the transcriptional transactivation function of the TP53 protein in a temperature sensitive manner (da Costa 2012 PMID: 23165212, Jia 1997 PMID: 9290701, Dearth 2007 PMID: 16861262, Ponchel 1998 PMID: 9635828, Jagosova 2012 PMID: 22710932); however, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant LFS. DISEASE. ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP3, PS3_Supporting.
Myriad Genetics, Inc.	RCV001527085	SCV004933200	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-20	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 7651740, 9635828, 15037740, 16861262]. This variant is expected to disrupt protein structure [Myriad internal data].
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000457645	SCV005689580	pathogenic	Li-Fraumeni syndrome	2025-02-04	criteria provided, single submitter	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785341	SCV000923909	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research