ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1276+7A>G (rs748554540)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204444 SCV000259564 likely benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000600314 SCV000713977 likely benign not specified 2017-07-03 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color RCV000776439 SCV000911925 likely benign Hereditary cancer-predisposing syndrome 2017-11-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000600314 SCV000917694 uncertain significance not specified 2018-03-21 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1276+7A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict an impact on normal splicing: Three predict the variant strengthens a cryptic 5' donor site, while one predicts the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 245846 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (1.2e-05 vs 0.00057), allowing no conclusion about variant significance. The variant, c.1276+7A>G, has been reported in the literature in one individual affected with Lynch Syndrome without strong evidence for causality. This report does 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. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) classifies the variant as "likely benign." Based on the evidence outlined above, the variant was classified as uncertain significance.

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