ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1525G>C (p.Val509Leu) (rs876660317)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000218406 SCV000277644 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000466630 SCV000551060 uncertain significance Hereditary nonpolyposis colon cancer 2018-03-16 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 509 of the MSH6 protein (p.Val509Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with endometrial cancer (PMID: 27443514). ClinVar contains an entry for this variant (Variation ID: 233297) Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000481397 SCV000571092 uncertain significance not provided 2018-03-06 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1525G>C at the cDNA level, p.Val509Leu (V509L) at the protein level, and results in the change of a Valine to a Leucine (GTG>CTG). This variant has been observed in at least one individual with endometrial cancer (Ring 2016). MSH6 Val509Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the mismatch binding domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Val509Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000218406 SCV000690205 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-05 criteria provided, single submitter clinical testing

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