ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.184C>T (p.Gln62Ter) (rs63751428)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075379 SCV000106374 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Ambry Genetics RCV000217644 SCV000274263 pathogenic Hereditary cancer-predisposing syndrome 2018-02-06 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 RCV000254916 SCV000321894 pathogenic not provided 2017-04-14 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.184C>T at the cDNA level and p.Gln62Ter (Q62X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA), 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 multiple families meeting Amsterdam Criteria and/or Bethesda Guidelines for Lynch syndrome (Liu 1995, Mangold 2005, Sjursen 2010) and is considered pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075379 SCV000592333 pathogenic Lynch syndrome 2013-08-29 criteria provided, single submitter clinical testing
Invitae RCV000694109 SCV000822538 pathogenic Hereditary nonpolyposis colon cancer 2018-10-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln62*) in the MLH1 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 several individuals and families affected with Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) (PMID: 8521398, 10323887, 15849733, 12362047, 20587412). ClinVar contains an entry for this variant (Variation ID: 89902). Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000075379 SCV000919646 pathogenic Lynch syndrome 2018-05-31 criteria provided, single submitter clinical testing Variant summary: MLH1 c.184C>T (p.Gln62X) 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 was absent in 246206 control chromosomes (in gnomAD). c.184C>T has been reported in the literature in multiple individuals from several families meeting Amsterdam Criteria for Lynch Syndrome (Lamberti 1999, Sjursen 2010). These data indicate that the variant is very likely to be associated with disease. In one of these studies it was experimentally confirmed that the variant of interest causes protein truncation (Lamberti 1999), moreover tumor IHC from several samples indicated missing MLH1/PMS2 protein (Sjursen 2010). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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.