ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1387G>A (p.Val463Met) (rs1064793825)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478449 SCV000567124 uncertain significance not provided 2015-07-08 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1387G>A at the cDNA level and p.Val463Met (V463M) 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. MSH2 Val463Met 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. MSH2 Val463Met occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located in the Clamp domain, which interacts with MSH6 and MSH3 and stabilizes interaction with EXO1 (Lützen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH2 Val463Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000572368 SCV000669708 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-28 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000572368 SCV000904252 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-17 criteria provided, single submitter clinical testing
Invitae RCV001210873 SCV001382382 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-07-03 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 463 of the MSH2 protein (p.Val463Met). The valine residue is highly 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 MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 419371). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; 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.

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