ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2439G>C (p.Met813Ile) (rs587781678)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000777250 SCV000912951 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-13 criteria provided, single submitter clinical testing
Invitae RCV000807280 SCV000947325 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-08-20 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 813 of the MSH2 protein (p.Met813Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine 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 conditions. 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 RCV001175571 SCV001339203 uncertain significance not specified 2020-03-09 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2439G>C (p.Met813Ile) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal InterPro (IPR000432) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251316 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.2439G>C in individuals affected with Lynch Syndrome has been reported. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Arora_2017). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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