ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3173-1G>C (rs397515875)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115404 SCV000216621 pathogenic Hereditary cancer-predisposing syndrome 2017-06-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000697257 SCV000825857 pathogenic Hereditary nonpolyposis colon cancer 2018-07-03 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 4 of the MSH6 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Lynch syndrome-associated cancers in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 42469). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035322 SCV000058970 likely pathogenic Lynch syndrome 2011-09-21 criteria provided, single submitter clinical testing The 3173-1G>C variant has not been previously reported and has not been previously identified by our laboratory. The 3173-1G>C variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the highly conserved splice consensus sequence. Computational splicing models predict this alteration to abolish the 3’ acceptor splice site of intron 4 and result in both intron 4 retention and exon 5 skipping; however, the accuracy of these models is not known. Although this variant is consistent with a loss of function allele, additional family-based and functional studies are required to fully assess the impact of this variant. Together, the evidence suggests this variant is likely to be pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000201971 SCV000257238 likely pathogenic not provided no assertion criteria provided research

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