ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2005+1G>A (rs267607986)

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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) RCV000076337 SCV000107361 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000078422 SCV000110273 pathogenic not provided 2017-09-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV001014038 SCV001174697 pathogenic Hereditary cancer-predisposing syndrome 2019-06-13 criteria provided, single submitter clinical testing The c.2005+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 12 of the MSH2 gene. This alteration was first reported in an individual whose family history met Amsterdam criteria for Lynch syndrome and colorectal tumor displayed high microsatellite instability (MSI-H) with positive expression of MSH2 on immunohistochemistry (IHC) (Bécouarn Y et al. Gastroenterol. Clin. Biol. 2005;29:667-75). This alteration has also been described in a family with Lynch syndrome (Bonadona V et al. JAMA 2011 Jun;305:2304-10). 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 []). Furthermore, this alteration has been identified in individuals whose Lynch syndrome- associated tumors were MSI-H and/or displayed absent expression of both MSH2/MSH6 on IHC (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. 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 RCV001068056 SCV001233145 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-09-17 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 12 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 observed in individual(s) with clinical features of Lynch syndrome (PMID: 16142001, 21642682, Invitae). ClinVar contains an entry for this variant (Variation ID: 90835). 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.

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