ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.643A>G (p.Ser215Gly) (rs886039484)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255449 SCV000322124 likely pathogenic not provided 2018-08-06 criteria provided, single submitter clinical testing This variant is denoted TP53 c.643A>G at the cDNA level, p.Ser215Gly (S215G) at the protein level, and results in the change of a Serine to a Glycine (AGT>GGT). TP53 Ser215Gly has not been reported in the literature as a germline variant to our knowledge, but has been reported as a somatic variant in various tumors including breast, brain, and hematologic cancers (Forbes 2015, Bouaoun 2016). This variant has been found to result in decreased transactivation of typical TP53 response elements (Grochova 2008, Slovackova 2010). 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 Ser215Gly was not observed in large population cohorts (Lek 2016). This variant is located in 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 Ser215Gly to be a likely pathogenic variant.
Invitae RCV000700891 SCV000829668 uncertain significance Li-Fraumeni syndrome 2019-07-08 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 215 of the TP53 protein (p.Ser215Gly). The serine residue is highly conserved and there is a small physicochemical difference between serine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with ovarian cancer (PMID: 30216591) and in a family affected with clinical features of Li-Fraumeni syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 265337). This variant has been reported to affect TP53 protein function (PMID: 17724467, 12826609, 12792784, 22862161) 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 Health, Inc RCV000772138 SCV000905241 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV000772138 SCV001187417 likely pathogenic Hereditary cancer-predisposing syndrome 2019-11-18 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 majority of available evidence to date, this variant is likely to be pathogenic.
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 Adenocarcinoma of stomach 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 Center Cologne,University Hospital Cologne RCV000785239 SCV000923807 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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