ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1662-2A>G (rs267607971)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076225 SCV000107249 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Invitae RCV000560516 SCV000625295 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-02-04 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 10 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 families affected with Lynch syndrome (PMID: 16810763, 21642682). ClinVar contains an entry for this variant (Variation ID: 90728). A different variant affecting this nucleotide (c.1662-2A>C) has been determined to be pathogenic (PMID: 18566915, 24090359). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001526860 SCV000919688 pathogenic Hereditary nonpolyposis colon cancer 2021-05-24 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1662-2A>G 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: Two predict that the variant abolishes a 3-prime acceptor site. One predicts that the variant creates a 5-prime donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250122 control chromosomes. c.1662-2A>G has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (e.g. Wang_2006, Bonadona_2011, Rossi_2017). 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 otherClinVar submitters (evaluation after 2014), including one expert panel, have cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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