ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3438+1G>A

dbSNP: rs267608096
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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) RCV000074854 SCV000108066 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Ambry Genetics RCV002453381 SCV002615189 pathogenic Hereditary cancer-predisposing syndrome 2022-04-27 criteria provided, single submitter clinical testing The c.3438+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 5 of the MSH6 gene. This variant has been reported in an individual with MSI-H rectal cancer diagnosed at age 45 and meeting Amsterdam criteria. It was also reported in an individual diagnosed with MSI-H colon cancer at ag 43, ovarian cancer at age 43, and endometrial cancer at age 53 (Overbeek LI et al. Br J Cancer, 2007 May;96:1605-12). This variant was shown by minigene assay to result in out of frame skipping of exon 5 (van der Klift HM et al. Mol Genet Genomic Med, 2015 Jul;3:327-45). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc. RCV003450967 SCV004189274 likely pathogenic Lynch syndrome 5 2023-08-23 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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