ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1276+2T>C (rs267607953)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000202216 SCV000292623 pathogenic not provided 2019-08-22 criteria provided, single submitter clinical testing Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 16395668, 30612635, 29625052)
Invitae RCV000460835 SCV000548099 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-10-12 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 7 of the MSH2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs267607953, ExAC 0.002%). Disruption of this splice site has been observed in individuals affected with Lynch syndrome associated tumors (PMID: 16395668, 21642682, 19669161, 21520333, Invitae). ClinVar contains an entry for this variant (Variation ID: 218032). 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 RCV000492023 SCV000580619 pathogenic Hereditary cancer-predisposing syndrome 2018-10-29 criteria provided, single submitter clinical testing The c.1276+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 7 in the MSH2 gene. This alteration was seen in a family meeting Amsterdam criteria (Ambry internal data). 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 pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202216 SCV000601428 pathogenic not provided 2016-12-23 criteria provided, single submitter clinical testing
Counsyl RCV000576479 SCV000677828 likely pathogenic Lynch syndrome I 2016-12-14 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000202216 SCV000257131 likely pathogenic not provided no assertion criteria provided research
MutSpliceDB: a database of splice sites variants effects on splicing,NIH RCV000202216 SCV001752427 not provided not provided no assertion provided in vivo

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