ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.283G>A (p.Val95Ile) (rs1323488764)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000819874 SCV000960559 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-11-04 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 95 of the MSH2 protein (p.Val95Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. 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 disease. 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.
Integrated Genetics/Laboratory Corporation of America RCV001175573 SCV001339205 uncertain significance not specified 2020-03-24 criteria provided, single submitter clinical testing Variant summary: MSH2 c.283G>A (p.Val95Ile) results in a conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal (IPR007695) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251262 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.283G>A in individuals affected with Hereditary Non-Polyposis Colon Cancer and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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