ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.943-1G>T (rs12476364)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000468897 SCV000548146 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-08-21 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 5 of the MSH2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several families with suspected Lynch syndrome (PMID: 28874130). ClinVar contains an entry for this variant (Variation ID: 408461). Different variants affecting this nucleotide (c.943-1G>A and c.943-1G>C) have been reported in the literature in individuals affected with Lynch syndrome (PMID: 11151427, 20233461, 26866578, 15849733). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000491423 SCV000580403 pathogenic Hereditary cancer-predisposing syndrome 2017-05-10 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Other strong data supporting pathogenic classification;Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985819 SCV001134381 pathogenic not provided 2019-03-27 criteria provided, single submitter clinical testing The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Integrated Genetics/Laboratory Corporation of America RCV001194032 SCV001363268 pathogenic Hereditary nonpolyposis colon cancer 2019-11-29 criteria provided, single submitter clinical testing Variant summary: MSH2 c.943-1G>T 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: Five predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251346 control chromosomes (gnomAD). c.943-1G>T has been reported in the literature in individuals affected with Lynch Syndrome (Rossi_2017, Cruz-Correa_2015). Other variants affecting the same nucleotide (c.943-1G>C and c.943-1G>A) have been classified as likely pathogenic by the InSiGHT expert panel in ClinVar (IDs: 91253 and 91252). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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