ClinVar Miner

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

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000772138 SCV000905241 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-19 criteria provided, single submitter clinical testing
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 Neoplasm of the breast 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 cancer 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
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.
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785239 SCV000923807 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Invitae RCV000700891 SCV000829668 uncertain significance Li-Fraumeni syndrome 2018-07-23 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 not been reported in the literature in the germline of individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 265337). Experimental studies in yeast have shown that this missense change results in temperature-dependent reduction of TP53 protein conformation and impaired transcriptional transactivation activity of the TP53 protein (PMID: 17724467, 12826609, 12792784). Additional studies in yeast have also shown that cells expressing this variant undergo apoptosis at a low frequency (PMID: 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.

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