Submissions for variant NM_000546.6(TP53):c.646G>A (p.Val216Met)

dbSNP: rs730882025

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000161067	SCV000211801	pathogenic	not provided	2023-11-21	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: severely impacted transcriptional activation and expression of typical p53 targets as well as impaired growth suppression ability (PMID: 12826609, 30224644, 29979965, 20505364, 17724467, 21232794); Identified in patients with history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx and in published literature (PMID: 32658383, 35974385, 28472496, 26014290); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21232794, 26014290, 20364130, 12826609, 18348286, 26619011, 16322298, 26567765, 25669829, 10949938, 19850740, 26787237, 11590071, 12673679, 28472496, 24549055, 17724467, 30720243, 30840781, 29979965, 15510160, 30224644, 32658383, 35974385, 20505364, 28369373)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168150	SCV000218811	pathogenic	Li-Fraumeni syndrome	2023-08-28	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). 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. ClinVar contains an entry for this variant (Variation ID: 182965). This missense change has been observed in individuals with breast and/or ovarian cancer and clinical features of Li-Fraumeni syndrome (PMID: 24549055, 25669829, 26014290; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 216 of the TP53 protein (p.Val216Met). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000561534	SCV000664416	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-16	criteria provided, single submitter	clinical testing	The p.V216M pathogenic mutation (also known as c.646G>A), located in coding exon 5 of the TP53 gene, results from a G to A substitution at nucleotide position 646. The valine at codon 216 is replaced by methionine, an amino acid with highly similar properties. This variant was previously detected in a child diagnosed with adrenocorticol carcinoma and in an individual with a personal history of alveolar rhabdomyosarcoma and soft tissue sarcoma (Bougeard G et al. J. Clin. Oncol. 2015 Jul;33:2345-52; Zerdoumi Y et al. Hum Mol Genet, 2017 07;26:2812). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (IARC TP53 database: 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). Based on internal structural analysis, this variant results in destabilization of the TP53 DNA binding domain (Kitayner M et al. Nat. Struct. Mol. Biol. 2010 Apr;17:423-9). 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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analyses. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV000561534	SCV000691605	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-01-14	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 216 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 defective in transactivation assays (PMID: 12826609, 17724467, 19850740, 21232794) and in human cell growth assays (PMID: 29979965, 30224644). This variant has been reported in individuals satisfying the Chompret criteria for Li-Fraumeni syndrome (PMID: 26014290, 28369373, 32658383). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	RCV000168150	SCV001449165	pathogenic	Li-Fraumeni syndrome	2020-09-17	criteria provided, single submitter	clinical testing	Data included in classification: UK family: 4 generation classic LFS family including multiple sarcomas Literature: (i) Bougeard 2015: 1 child (?age) with ACC , (ii) Zerdoumi 2017: 1 adult male age 30y with alveloar rhabdo age 3y & soft tissue sarcoma age 17y. Both index cases & fulfil Chompret (nil known re FHx) (PS4_mod). This variant is absent from gnomAD (PM2_sup). AGvGD = C15 , Bayes Del = 0.5501. PP3_sup. x81 somatic in IARC (PM1_sup). Kato – non functional, DNE + LOF (Giacomelli) , Kotler - RFS score = 0.2 → compromised function. (PS3_strong)
Genetic Services Laboratory, University of Chicago	RCV000161067	SCV002067403	likely pathogenic	not provided	2019-11-25	criteria provided, single submitter	clinical testing	DNA sequence analysis of the TP53 gene demonstrated a sequence change, c.646G>A, in exon 6 that results in an amino acid change, p.Val216Met. The p.Val216Met change has not been described in population databases (gnomAD, ExAC). This sequence change has been identified in a child with adrenocortical carcinoma (PMID: 26014290). Functional studies revealed that the p.Val216Met change results in a drastic change of p53 transcriptional activity, similar to that of dominant-negative mutations (PMID: 28369373). The p.Val216Met change affects a highly conserved amino acid residue located in a domain of the TP53 protein that is known to be functional. The p.Val216Met substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL)." DNA sequence analysis of the TP53 gene demonstrated a sequence change, c.646G>A, in exon 6 that results in an amino acid change, p.Val216Met. The p.Val216Met change has not been described in population databases (gnomAD, ExAC). This sequence change has been identified in a child with adrenocortical carcinoma (PMID: 26014290). Functional studies revealed that the p.Val216Met change results in a drastic change of TP53 transcriptional activity, similar to that of dominant-negative mutations (PMID: 28369373). The p.Val216Met change affects a highly conserved amino acid residue located in a domain of the TP53 protein that is known to be functional. The p.Val216Met substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL).
Myriad Genetics, Inc.	RCV000663213	SCV004017859	likely pathogenic	Li-Fraumeni syndrome 1	2023-04-11	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].
Baylor Genetics	RCV003474837	SCV004204290	likely pathogenic	Adrenocortical carcinoma, hereditary	2021-09-29	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000168150	SCV004847704	likely pathogenic	Li-Fraumeni syndrome	2019-04-02	criteria provided, single submitter	clinical testing	The p.Val216Met variant in TP53 has been reported in two individuals with TP53-related tumors and one individual with a family history of TP53-related tumors (Castera 2014, Bougeard 2015, Zerdoumi 2017). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 182965). It has also been reported as a common somatic mutation across multiple tumor types (COSMIC Database, https://cancer.sanger.ac.uk/cosmic/). In vitro functional studies provide some evidence that this variant impacts protein transactivation function (Slovackova 2010, Zerdoumi 2017); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis support that this variant may impact the protein. 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 Li-Fraumeni syndrome. ACMG/AMP Criteria applied: PM2, PS3_Moderate, PP3, PS4_Supporting.
Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili	RCV000663213	SCV005200617	pathogenic	Li-Fraumeni syndrome 1	2024-08-16	criteria provided, single submitter	clinical testing
Database of Curated Mutations (DoCM)	RCV000424101	SCV000509906	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428263	SCV000509907	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438503	SCV000509908	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421726	SCV000509909	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431843	SCV000509910	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444190	SCV000509911	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421819	SCV000509912	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432944	SCV000509913	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443170	SCV000509914	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426366	SCV000509915	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436614	SCV000509916	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Mayo Clinic Laboratories, Mayo Clinic	RCV000583984	SCV000692077	uncertain significance	not specified		no assertion criteria provided	clinical testing
Counsyl	RCV000663213	SCV000786399	uncertain significance	Li-Fraumeni syndrome 1	2018-04-25	flagged submission	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785523	SCV000924095	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research