ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.943-1G>C (rs12476364)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076758 SCV000107799 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Ambry Genetics RCV000491758 SCV000580427 pathogenic Hereditary cancer-predisposing syndrome 2017-11-28 criteria provided, single submitter clinical testing The c.943-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 6 of the MSH2 gene. This variant was detected in several individuals meeting either Bethesda or Amsterdam II criteria for Lynch syndrome (Ambry internal data; Mangold E et al. Int. J. Cancer 2005;116(5):692-702). In addition, this alteration has been identified in individuals exhibiting high microsatellite instability (MSI-H) and/or loss of MSH2 expression on immunohistochemistry (IHC) in their colorectal tumors (Ambry internal data; Mangold E et al. J Pathol. 2005 Dec;207(4):385-95). This alteration has been classified as likely pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). Another pathogenic variant at the same position, c.943-1G>T, was identified in several individuals exhibiting loss of MSH2 as well as MSH6 in their colorectal/endometrial tumors on IHC and had family histories that met Amsterdam I/II criteria for Lynch syndrome (Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Invitae RCV000696831 SCV000825410 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-02-29 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). Disruption of this splice site has been reported in individuals with clinical features of Lynch syndrome (PMID: 15849733, 28874130, 11151427, Invitae). ClinVar contains an entry for this variant (Variation ID: 91253). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001531920 SCV001747251 pathogenic not provided 2021-06-01 criteria provided, single submitter clinical testing

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