ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.646G>A (p.Val216Met) (rs730882025)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx 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 likely pathogenic Li-Fraumeni syndrome 2020-10-01 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 216 of the TP53 protein (p.Val216Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 26014290, Invitae). Additionally, this variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 24549055, 25669829). Clinvar contains an entry for this variant (Variation ID: 182965). Experimental studies in yeast have shown that this variant impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609, 17724467, 21232794). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000561534 SCV000664416 likely pathogenic Hereditary cancer-predisposing syndrome 2020-03-16 criteria provided, single submitter clinical testing The p.V216M variant (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 (Bougeard G et al. J. Clin. Oncol. 2015 Jul;33:2345-52). 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 (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 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 majority of available evidence to date, this variant is likely to be pathogenic.
Color Health, Inc 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.
Counsyl RCV000663213 SCV000786399 uncertain significance Li-Fraumeni syndrome 1 2018-04-25 criteria provided, single submitter clinical testing
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)
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
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785523 SCV000924095 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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