ClinVar Miner

Submissions for variant NM_002439.5(MSH3):c.238-2A>G

gnomAD frequency: 0.00001  dbSNP: rs1749285874
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001219744 SCV001391697 likely pathogenic not provided 2024-05-15 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 1 of the MSH3 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 948482). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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.
Ambry Genetics RCV003163691 SCV003856394 likely pathogenic Hereditary cancer-predisposing syndrome 2024-09-18 criteria provided, single submitter clinical testing The c.238-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 2 in the MSH3 gene. This nucleotide position is highly conserved in available vertebrate species. 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. 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.
Myriad Genetics, Inc. RCV003458644 SCV004189037 likely pathogenic Familial adenomatous polyposis 4 2023-08-29 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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