ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.467C>G (p.Ser156Ter) (rs63749873)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075003 SCV000108220 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Pathway Genomics RCV000172813 SCV000223779 pathogenic Lynch syndrome I 2014-10-30 criteria provided, single submitter clinical testing
GeneDx RCV000201956 SCV000279092 pathogenic not provided 2018-12-26 criteria provided, single submitter clinical testing This pathogenic variant is denoted MSH6 c.467C>G at the cDNA level and p.Ser156Ter (S156X) 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. This variant has been observed in several individuals meeting Amsterdam or Bethesda criteria, whose tumors often exhibited microsatellite instability and lacked expression of the MSH6 protein on immunohistochemistry (Winjen 1999, Plaschke 2004, Stormorken 2005, Overbeek 2007, van Puijenbroek 2008, Sjursen 2010, Leenan 2012, van Lier 2012). MSH6 p.Ser156Ter was found to segregate with disease in at least one family (Pallauf 2012). We consider this variant to be pathogenic.
Invitae RCV000524207 SCV000551041 pathogenic Hereditary nonpolyposis colon cancer 2019-12-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser156*) 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 individuals affected with rectal cancer and ovarian cancer (PMID: 15483016, 24728189), and in numerous individuals and families with Lynch syndrome (PMID: 10508506, 18301448, 22081473, 16034045, 17453009, 18625694). This variant has also been described as a founder mutation in the Netherlands, causing Lynch syndrome in individuals of Dutch ancestry (PMID: 18625694). ClinVar contains an entry for this variant (Variation ID: 89534). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000490955 SCV000580104 pathogenic Hereditary cancer-predisposing syndrome 2018-09-24 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Counsyl RCV000576312 SCV000677750 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2017-02-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000201956 SCV000888290 pathogenic not provided 2018-04-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000075003 SCV000917758 pathogenic Lynch syndrome 2019-04-15 criteria provided, single submitter clinical testing Variant summary: MSH6 c.467C>G (p.Ser156X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.718C>T (p.Arg240X), c.742C>T(p.Arg248X)). The variant allele was found at a frequency of 8e-06 in 251286 control chromosomes (gnomAD and DeRycke_2017) and has been reported in the literature in multiple individuals affected with colon cancer, pancreatic cancer and constitutional mismatch repair deficiency syndrome (Wijnen_1999, Steinke_2008, vanLier_2012, DeRycke_2017, Hu_2018, Tesch_2018). These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000201956 SCV001250444 pathogenic not provided 2018-05-01 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000201956 SCV000257301 pathogenic not provided no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.