Submissions for variant NM_000546.6(TP53):c.643A>G (p.Ser215Gly)

dbSNP: rs886039484

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255449	SCV000322124	likely pathogenic	not provided	2019-07-12	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 17724467, 15138567, 14559903, 8361764, 12792784, 20505364, 30216591, 29979965, 30720243, 30840781)
Invitae	RCV000700891	SCV000829668	uncertain significance	Li-Fraumeni syndrome	2024-01-25	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 individual(s) with clinical features of Li-Fraumeni syndrome and/or ovarian cancer (PMID: 30216591; Invitae). ClinVar contains an entry for this variant (Variation ID: 265337). 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 with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000772138	SCV000905241	uncertain significance	Hereditary cancer-predisposing syndrome	2018-10-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000772138	SCV001187417	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-19	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.
Sema4, Sema4	RCV000772138	SCV002532696	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-05-06	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282093	SCV002572405	uncertain significance	not specified	2022-08-29	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. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251466 control chromosomes (gnomAD). c.643A>G has been reported in the literature in the germline of individuals affected with Ovarian cancer (Weber-Lassalle_2018) and Gastric cancer (Chen_2011). These data do not allow any conclusion about variant significance. In cancer cell culture proliferation/survival assays, the variant was found to have reduced apoptotic activity compared to wild-type Tp53 when introduced to cancer cell lines, but had greater activity when compared to null variants (Slovackova_2012, Kotler_2018). Six ClinVar submitters have assessed the variant since 2014: four classified the variant as likely pathogenic and two as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Myriad Genetics, Inc.	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].
Database of Curated Mutations (DoCM)	RCV000445278	SCV000509668	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427564	SCV000509669	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436667	SCV000509670	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419408	SCV000509671	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430142	SCV000509672	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437324	SCV000509673	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418361	SCV000509674	likely pathogenic	Small cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429054	SCV000509675	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439730	SCV000509676	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785239	SCV000923807	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research