ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3801+1G>T

gnomAD frequency: 0.00001  dbSNP: rs876660943
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000217114 SCV000278763 likely pathogenic Hereditary cancer-predisposing syndrome 2024-07-12 criteria provided, single submitter clinical testing The c.3801+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 8 of the MSH6 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000226322 SCV000283816 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2023-03-21 criteria provided, single submitter clinical testing Studies have shown that disruption of this splice site results in skipping of exon 8 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. ClinVar contains an entry for this variant (Variation ID: 234228). This sequence change affects a donor splice site in intron 8 of the MSH6 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 MSH6-related conditions.
Fulgent Genetics, Fulgent Genetics RCV000763498 SCV000894284 likely pathogenic Endometrial carcinoma; Mismatch repair cancer syndrome 1; Lynch syndrome 5 2018-10-31 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV003137829 SCV003828332 likely pathogenic not provided 2023-01-30 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV003454661 SCV004189258 likely pathogenic Lynch syndrome 5 2023-08-25 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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