ClinVar Miner

Submissions for variant NM_001281492.1(MSH6):c.3124dup (p.Arg1042fs) (rs63751327)

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) RCV000074872 SCV000108084 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Ambry Genetics RCV000166347 SCV000217134 pathogenic Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000627713 SCV000283809 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-12-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1172Lysfs*5) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs63751327, ExAC 0.001%). This variant has been observed in families with suspected Lynch syndrome (PMID: 10508506, 18566915, 20587412) and in individuals affected with urothelial, colorectal, bladder and ovarian cancer (PMID: 20591884, 20682701, 24728189, 19130300). This variant is also known as 1172insA or c.3514_3515insA in the literature. ClinVar contains an entry for this variant (Variation ID: 89404). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000409599 SCV000488032 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2015-12-16 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000074872 SCV000592646 pathogenic Lynch syndrome 2014-01-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202194 SCV000888277 pathogenic not provided 2015-10-08 criteria provided, single submitter clinical testing
Color RCV000166347 SCV000905457 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000074872 SCV000917779 pathogenic Lynch syndrome 2018-10-19 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3514dupA (p.Arg1172LysfsX5) 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. The variant allele was found at a frequency of 1.1e-05 in 277060 control chromosomes (gnomAD). c.3514dupA has been reported in the literature in multiple individuals affected with Lynch Syndrome or related tumor phenotypes (Nilbert 2009, Schofield 2009, Sjursen 2010, Steinke2008, Wijnen 1999, Plaschke 2004, Haraldsdottir 2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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.
GeneDx RCV000202194 SCV001168605 pathogenic not provided 2018-12-19 criteria provided, single submitter clinical testing This duplication of one nucleotide in MSH6 is denoted c.3514dupA at the cDNA level and p.Arg1172LysfsX5 (R1172KfsX5) at the protein level. The normal sequence, with the base that is duplicated in brackets, is TGAT[dupA]GAGT. The duplication causes a frameshift which changes an Arginine to a Lysine at codon 1172, and creates a premature stop codon at position 5 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH6 c.3514dupA, also reported as MSH6 3514insA, has been reported in individuals meeting Bethesda guidelines and Amsterdam criteria for Lynch syndrome. (Plaschke 2004 , Overbeek 2007, Nilbert 2009, Sjursen 2010, van der Post 2010, Haraldsdottir 2017). This variant was also observed in the compound heterozygous state in an individual with constitutional mismatch repair deficiency (CMMR-D) syndrome (Soplepmann 2016). We consider this variant to be pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202194 SCV000257260 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.