Total submissions: 19
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 | likely pathogenic | Li-Fraumeni syndrome | 2019-12-11 | 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 | RCV000561534 | SCV000691605 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-04-08 | criteria provided, single submitter | clinical testing | |
Counsyl | RCV000663213 | SCV000786399 | uncertain significance | Li-Fraumeni syndrome 1 | 2018-04-25 | criteria provided, single submitter | clinical testing | |
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) |
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 Genetic Testing Laboratories, |
RCV000583984 | SCV000692077 | uncertain significance | not specified | no assertion criteria provided | clinical testing | ||
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne, |
RCV000785523 | SCV000924095 | likely pathogenic | Neoplasm of ovary | 2018-12-01 | no assertion criteria provided | research |