ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.4001+2T>C (rs267608131)

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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) RCV000074969 SCV000108185 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant causes splicing aberration, >2 MSI-H, co-segregation with disease & absent in 1000 genomes
Ambry Genetics RCV000491060 SCV000580113 pathogenic Hereditary cancer-predisposing syndrome 2018-04-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000812440 SCV000952753 likely pathogenic Hereditary nonpolyposis colon cancer 2018-11-07 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in the last intron (intron 9) of the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with disease in a Lynch syndrome family and has been observed in several individuals and families with suspected Lynch syndrome (PMID: 18566915, 21836479, 25648859, 22495361). ClinVar contains an entry for this variant (Variation ID: 89501). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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