ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.792+1delG (rs1064794155)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491720 SCV000580478 pathogenic Hereditary cancer-predisposing syndrome 2016-01-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
GeneDx RCV000485573 SCV000568005 pathogenic not provided 2015-09-18 criteria provided, single submitter clinical testing This pathogenic variant is denoted MSH2 c.792+1delG or IVS4+1delG and consists of a single nucleotide deletion at the +1 position of intron 4 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.792+1delG to be pathogenic.
Invitae RCV000525827 SCV000625463 likely pathogenic Hereditary nonpolyposis colon cancer 2017-06-29 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 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 individuals in the Universal Mutation Database (PMID: 10612827).  ClinVar contains an entry for this variant (Variation ID: 419862). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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