ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492023 SCV000580619 pathogenic Hereditary cancer-predisposing syndrome 2016-07-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Counsyl RCV000576479 SCV000677828 likely pathogenic Lynch syndrome I 2016-12-14 criteria provided, single submitter clinical testing
GeneDx RCV000202216 SCV000292623 pathogenic not provided 2018-10-23 criteria provided, single submitter clinical testing This pathogenic variant is denoted MSH2 c.1276+2T>C or IVS7+2T>C and consists of a T>C nucleotide substitution at the +2 position of intron 7 of the MSH2 gene. The variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published in the literature. Based on the current evidence, we consider MSH2 c.1276+2T>C to be pathogenic.
Invitae RCV000460835 SCV000548099 pathogenic Hereditary nonpolyposis colon cancer 2017-08-08 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%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 218032). A different variant affecting this nucleotide (c.1276+2T>A) has been determined to be pathogenic (PMID: 16395668, 21642682). 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202216 SCV000257131 likely pathogenic not provided no assertion criteria provided research
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202216 SCV000601428 pathogenic not provided 2016-12-23 criteria provided, single submitter clinical testing

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