Total submissions: 13
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Institute for Genomic Medicine |
RCV006253934 | SCV007104797 | tier i - strong | Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype | 2022-11-07 | criteria provided, single submitter | clinical testing | Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant. 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24705254, 28912153, 34848827). |
| Myriad Genetics, |
RCV004021028 | SCV004933099 | likely pathogenic | Li-Fraumeni syndrome 1 | 2024-02-15 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965, 14559903, 20505364]. This variant is expected to disrupt protein structure [Myriad internal data]. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002282093 | SCV002572405 | uncertain significance | not specified | 2026-01-15 | criteria provided, single submitter | clinical testing | Variant summary: TP53 c.643A>G (p.Ser215Gly) results in a non-conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 251466 control chromosomes. c.643A>G has been observed in individuals affected with Ovarian cancer or clinical features of Li-Fraumeni syndrome (Weber-Lassalle_2018, internal data) and Gastric cancer (Chen_2011). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Slovackova_2012, Kotler_2018). The most pronounced variant effect results in reduced apoptotic activity compared to wild-type Tp53, but greater activity when compared to null variants when introduced to cancer cell lines. The following publications have been ascertained in the context of this evaluation (PMID: 23246812, 21080251, 27895058, 16818505, 11782540, 22915647, 26230955, 21519010, 20407015, 27463065, 29979965, 30327374, 17606709, 21343334, 26585234, 25952993, 27276561, 22186996, 22862161, 27680515, 30216591, 27959731). ClinVar contains an entry for this variant (Variation ID: 265337). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Sema4, |
RCV000772138 | SCV002532696 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2021-05-06 | criteria provided, single submitter | curation | |
| Ambry Genetics | RCV000772138 | SCV001187417 | pathogenic | Hereditary cancer-predisposing syndrome | 2025-05-19 | criteria provided, single submitter | clinical testing | The p.S215G variant (also known as c.643A>G), located in coding exon 5 of the TP53 gene, results from an A to G substitution at nucleotide position 643. The serine at codon 215 is replaced by glycine, an amino acid with similar properties. This variant has been identified in an individual with a history consistent with Li Fraumeni syndrome (Ambry internal data) as well as in an individual diagnosed with ovarian cancer at age 49 (Weber-Lassalle K et al. Hum. Mutat. 2018 12;39:2040-2046). This alteration has been shown to be temperature sensitive and have a loss of transactivation activity in yeast based functional studies (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. U.S.A., 2003 Jul;100:8424-9; Shiraishi K et al. J. Biol. Chem. 2004 Jan;279:348-55). Additional yeast based assays showed retained tranactivation for some but not all p53 response elements (Grochova D et al. Oncogene. 2008 Feb; 27:1243-52; Pavlova S et al. Int. J. Oncol. 2003 Jul;23:121-31). 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 is anticipated to result in a decrease in structural stability (Cho Y et al. Science. 1994 Jul; 265(5170):346-55). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Color Diagnostics, |
RCV000772138 | SCV000905241 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-10-19 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000700891 | SCV000829668 | pathogenic | Li-Fraumeni syndrome | 2025-10-27 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 215 of the TP53 protein (p.Ser215Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 30216591, 38702830; internal data). ClinVar contains an entry for this variant (Variation ID: 265337). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV000255449 | SCV000322124 | likely pathogenic | not provided | 2023-12-12 | criteria provided, single submitter | clinical testing | Reported as germline variant in an individual with ovarian cancer (PMID: 30216591); 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: 17724467, 15138567, 14559903, 8361764, 12792784, 20505364, 29979965, 30720243, 30840781, 34863587, 30224644, 17606709, 11782540, 16818505, 20407015, 33558336, 15510160, 34273903, 30216591) |
| Dr. |
RCV005895442 | SCV006900343 | not provided | Pancreatic adenocarcinoma | no classification provided | in vitro | ||
| Dr. |
RCV005895440 | SCV006900342 | not provided | Glioma susceptibility 1 | no classification provided | in vitro | ||
| Dr. |
RCV005895440 | SCV006900341 | not provided | Glioma susceptibility 1 | no classification provided | in vitro | ||
| Dr. |
RCV005895441 | SCV006900340 | not provided | Squamous cell lung carcinoma | no classification provided | in vitro | ||
| German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000785239 | SCV000923807 | likely pathogenic | Ovarian neoplasm | 2018-12-01 | no assertion criteria provided | research |