ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3768T>G (p.Tyr1256Ter) (rs63751058)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074926 SCV000108139 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Ambry Genetics RCV000491038 SCV000580173 pathogenic Hereditary cancer-predisposing syndrome 2017-09-13 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)
GeneDx RCV000202271 SCV000616790 pathogenic not provided 2018-04-09 criteria provided, single submitter clinical testing This pathogenic variant is denoted MSH6 c.3768T>G at the cDNA level and p.Tyr1256Ter (Y1256X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAT>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least three women with endometrial cancer, one of whom also had colorectal cancer, with studied tumors demonstrating microsatellite instability and/or loss of MSH6 protein expression on immunohistochemistry (Hampel 2006, Hampel 2007, Goodfellow 2015). We consider this variant to be pathogenic.
Invitae RCV000546623 SCV000624913 pathogenic Hereditary nonpolyposis colon cancer 2018-12-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr1256*) 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 in individuals affected with endometrial cancer and suspected Lynch syndrome (PMID: 16885385, 26552419, 25430799). ClinVar contains an entry for this variant (Variation ID: 89458). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202271 SCV000257278 pathogenic not provided no assertion criteria provided research

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