ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1511-1G>A (rs267607964)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000758599 SCV000919715 likely pathogenic Lynch syndrome 2018-08-31 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1511-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 3' acceptor site and introduces a cryptic 3' acceptor site 1bp into the exon. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 246146 control chromosomes (gnomAD). The variant, c.1511-1G>A, has been reported in the literature in individuals affected with Lynch Syndrome (Vargas-Parra_2017, Yurgelun_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
University of Washington Department of Laboratory Medicine,University of Washington RCV000758599 SCV000887353 pathogenic Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH2 NM_000251.2:c.1511-1G>A has a 99.4% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214.

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