ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1039_1040insC (p.Glu347fs) (rs1553412441)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000629779 SCV000750735 pathogenic Hereditary nonpolyposis colon cancer 2017-10-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu347Alafs*7) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related disease. 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 RCV000826200 SCV000967754 pathogenic Lynch syndrome 2017-10-09 criteria provided, single submitter clinical testing The p.Glu347AlafsX7 variant in MSH6 has not been previously reported in individu als with Lynch syndrome or in large population studies but was reported by anoth er clinical laboratory in ClinVar (Variation ID: 525645). This variant is predic ted to cause a frameshift, which alters the protein?s amino acid sequence beginn ing at position 347 and leads to a premature termination codon 7 amino acids dow nstream. This alteration is then predicted to lead to a truncated or absent prot ein. Heterozygous loss of function of the MSH6 gene is an established disease me chanism in individuals with Lynch syndrome. In summary, this variant meets crite ria to be classified as pathogenic for Lynch syndrome in an autosomal dominant m anner based upon the predicted impact to the protein and absence from the genera l population. ACMG/AMP criteria applied: PVS1, PM2.

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