ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2649T>G (p.Ile883Met) (rs768983827)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000580301 SCV000685068 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-21 criteria provided, single submitter clinical testing
Invitae RCV000629841 SCV000750797 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-02-02 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 883 of the MSH2 protein (p.Ile883Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs768983827, ExAC 0.01%). This variant has been reported in an individual affected with colorectal cancer (PMID: 19621678). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly 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.
Ambry Genetics RCV000580301 SCV001177130 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-15 criteria provided, single submitter clinical testing Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV001193286 SCV001362020 uncertain significance not specified 2019-01-18 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2649T>G (p.Ile883Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 276876 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2649T>G has been reported in the literature in an individual affected with Lynch Syndrome (Kang 2015, Lee 2018). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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