ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2621A>G (p.Tyr874Cys) (rs775390721)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000776212 SCV000911370 likely benign Hereditary cancer-predisposing syndrome 2015-09-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781567 SCV000919719 uncertain significance not specified 2018-09-24 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2621A>G (p.Tyr874Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 246210 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.2621A>G in individuals affected with Lynch Syndrome 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.
Invitae RCV000630014 SCV000750970 uncertain significance Hereditary nonpolyposis colon cancer 2018-04-29 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 874 of the MSH2 protein (p.Tyr874Cys). The tyrosine residue is weakly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs775390721, ExAC 0.006%). 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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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