ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1805C>G (p.Ser602Ter) (rs730881816)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491316 SCV000580257 pathogenic Hereditary cancer-predisposing syndrome 2016-12-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV000491316 SCV000905452 pathogenic Hereditary cancer-predisposing syndrome 2018-04-25 criteria provided, single submitter clinical testing
Counsyl RCV000409404 SCV000488387 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2016-03-16 criteria provided, single submitter clinical testing
GeneDx RCV000160715 SCV000211348 pathogenic not provided 2014-10-03 criteria provided, single submitter clinical testing This pathogenic variant is denoted MSH6 c.1805C>G at the cDNA level and p.Ser602Ter (S602X) at the protein level. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic.
Invitae RCV000627696 SCV000283729 pathogenic Hereditary nonpolyposis colon cancer 2018-12-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser602*) 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 been reported to segregate with cancers associated with Lynch syndrome in a family (Invitae). It has also been reported in an individual affected with renal cancer and a neuroectodermal tumor (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 182659). 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 RCV000231648 SCV000712558 pathogenic Lynch syndrome 2016-11-09 criteria provided, single submitter clinical testing The p.Ser602X variant in MSH6 has not been previously reported in individuals wi th Lynch Syndrome and was absent from large population studies. This nonsense va riant leads to a premature termination codon at position 602 which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the M SH6 gene is an established disease mechanism in Lynch Syndrome. In summary, this variant meets criteria to be classified as pathogenic for Lynch Syndrome in an autosomal dominant manner based upon the predicted impact to the protein.

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