ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.793-1G>C

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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 RCV002416795 SCV002677955 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-09 criteria provided, single submitter clinical testing The c.793-1G>C intronic variant results from a G to C substitution one nucleotide before coding exon 5 of the MSH2 gene. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (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 likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV003099794 SCV003247685 pathogenic Hereditary nonpolyposis colorectal neoplasms 2021-12-12 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individuals with Lynch syndrome (PMID: 20052760, 27601186; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 4 of the MSH2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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).
Myriad Genetics, Inc. RCV003454202 SCV004186670 likely pathogenic Lynch syndrome 1 2023-07-28 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.

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