ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1077-2A>G (rs267607943)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076024 SCV000107044 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Ambry Genetics RCV000491149 SCV000580643 pathogenic Hereditary cancer-predisposing syndrome 2017-06-02 criteria provided, single submitter clinical testing The c.1077-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 7 in the MSH2 gene. This intronic mutation has previously been reported in a German patient whose personal and family history was suspicious for HNPCC/Lynch syndrome and whose tumor was MSI-H with absent MSH2/MSH6 proteins on IHC (Mueller-Koch Y et al. Gut 2005 Dec;54(12):1733-40). 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 RCV000529751 SCV000625225 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-06-24 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 6 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 the literature in individuals affected with Lynch syndrome (PMID: 15849733, 20388775, 15955785). ClinVar contains an entry for this variant (Variation ID: 90529). 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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