ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.694C>T (p.Gln232Ter) (rs587779318)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075025 SCV000108246 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
GeneDx RCV000412800 SCV000490619 pathogenic not provided 2016-06-09 criteria provided, single submitter clinical testing This pathogenic variant is denoted MSH6 c.694C>T at the cDNA level and p.Gln232Ter (Q232X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant was reported in a recent study (Pritchard 2012) and is considered pathogenic.
Invitae RCV001383732 SCV001582985 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-03-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln232*) 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 observed in individual(s) with clinical features of Lynch syndrome (PMID: 22658618). ClinVar contains an entry for this variant (Variation ID: 89556). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000412800 SCV000592575 uncertain significance not provided no assertion criteria provided clinical testing The p.Gln232X variant has been reported in the literature in 1/120 proband chromosomes of an individual with Lynch syndrome (Pritchard 2012); it was not identified in any of the 38 control chromosomes. In addition, it has been previously identified in one family by our laboratory meeting MOH criteria for FAP. The variant was also identified in the InSiGHT Colon Cancer database. The variant leads to a premature stop codon at position 232 which is predicted to cause premature truncation or absent protein product and loss of function. Loss of function is an established disease mechanism for the MSH6 gene and is the type of variant expected to cause Lynch syndrome. In summary, based on the above information, this variant is classified as pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000412800 SCV001932243 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000412800 SCV001955648 pathogenic not provided no assertion criteria provided clinical testing

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