ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1957G>A (p.Val653Met) (rs768095444)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222892 SCV000277711 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000478131 SCV000569042 uncertain significance not provided 2016-11-22 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1957G>A at the cDNA level, p.Val653Met (V653M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Val653Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. MSH6 Val653Met occurs at a position that is not conserved and is located in domain II of the MutS domain (Terui 2013). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether MSH6 Val653Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000629954 SCV000750910 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 653 of the MSH6 protein (p.Val653Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 233357). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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