Total submissions: 22
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000161067 | SCV000211801 | pathogenic | not provided | 2018-07-13 | criteria provided, single submitter | clinical testing | This variant is denoted TP53 c.646G>A at the cDNA level, p.Val216Met (V216M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). TP53 Val216Met has been reported in an individual with multiple sarcomas, another with adrenocortical carcinoma, as well as an unaffected male from a family meeting Chompret criteria for Li-Fraumeni syndrome (Cast?ra 2014, Bougeard 2015, Zerdoumi 2017). Multiple functional assays have found this variant to severely impact transcriptional activation and expression of typical p53 targets (Grochova 2008, Malcikova 2009, Slovackova 2010, Pekova 2011). Consistent with these results, this variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Val216Met was not observed in large population cohorts (Lek 2016). This variant is located within the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available information, we consider TP53 Val216Met to be pathogenic. |
Invitae | 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, |
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, |
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, |
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, |
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 | |
Database of Curated Mutations |
RCV000424101 | SCV000509906 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000428263 | SCV000509907 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000438503 | SCV000509908 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000421726 | SCV000509909 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000431843 | SCV000509910 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
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 |
RCV000421819 | SCV000509912 | likely pathogenic | Ovarian serous cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432944 | SCV000509913 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000443170 | SCV000509914 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426366 | SCV000509915 | likely pathogenic | Squamous cell carcinoma of the skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436614 | SCV000509916 | likely pathogenic | Uterine carcinosarcoma | 2016-05-31 | no assertion criteria provided | literature only | |
Mayo Clinic Laboratories, |
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, |
RCV000785523 | SCV000924095 | likely pathogenic | Neoplasm of ovary | 2018-12-01 | no assertion criteria provided | research |