ClinVar Miner

Submissions for variant NM_002439.5(MSH3):c.358+2T>G

gnomAD frequency: 0.00001  dbSNP: rs1450314617
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000815764 SCV000956234 likely pathogenic not provided 2025-01-31 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 2 of the MSH3 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 MSH3 are known to be pathogenic (PMID: 27476653, 37402566). This variant is present in population databases (no rsID available, gnomAD 0.03%). 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: 658860). Studies have shown that disruption of this splice site is associated with inconclusive levels of altered splicing (internal data). 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.
Sema4, Sema4 RCV002255536 SCV002536521 likely pathogenic Hereditary cancer-predisposing syndrome 2021-09-28 criteria provided, single submitter curation
Ambry Genetics RCV002255536 SCV002613598 likely pathogenic Hereditary cancer-predisposing syndrome 2024-05-03 criteria provided, single submitter clinical testing The c.358+2T>G intronic variant results from a T to G substitution two nucleotides after 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 donor 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.
Myriad Genetics, Inc. RCV003458545 SCV004189019 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.
Baylor Genetics RCV003461236 SCV004197125 likely pathogenic Endometrial carcinoma 2024-03-22 criteria provided, single submitter clinical testing
GeneDx RCV000815764 SCV005439281 likely pathogenic not provided 2024-06-17 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics RCV005047101 SCV005673163 likely pathogenic Endometrial carcinoma; Familial adenomatous polyposis 4 2024-03-13 criteria provided, single submitter clinical testing

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