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

Total submissions: 19

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