ClinVar Miner

Submissions for variant NM_001167617.2(MLH1):c.1195dup (p.Arg399fs) (rs63750855)

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) RCV000075227 SCV000106219 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
GeneDx RCV000201993 SCV000211079 pathogenic not provided 2018-07-09 criteria provided, single submitter clinical testing This duplication of one nucleotide is denoted MLH1 c.1489dupC at the cDNA level and p.Arg497ProfsX6 (R497PfsX6) at the protein level. The normal sequence, with the base that is duplicated in brackets, is ACCCCC[dupC]GGAG. The duplication causes a frameshift, which changes an Arginine to a Proline at codon 497, and creates a premature stop codon at position 6 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. Also published as MLH1 c.1489_1490insC using alternate nomenclature, this variant has been reported in many individuals and families with Lynch syndrome (Kurzawski 2002, Behrens 2003, Mangold 2005, Wolf 2006, Bonadona 2011, Buchanan 2014, Magnani 2015). MLH1 c.1489dupC has also been reported in at least one individual with a clinical diagnosis of Muir-Torre syndrome (Mangold 2007). Additionally, this variant has been observed in the germline of at least two individuals with breast cancer; one breast tumor demonstrated loss of MLH1 protein on immunohistochemistry and the other breast tumor demonstrated loss of heterozygosity (Lotsari 2012, Pedroni 2014). Lastly, the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic (Thompson 2014). Based on currently available evidence, we consider MLH1 c.1489dupC to be pathogenic.
Ambry Genetics RCV000162490 SCV000212869 pathogenic Hereditary cancer-predisposing syndrome 2018-06-25 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Counsyl RCV000412044 SCV000489202 pathogenic Lynch syndrome II 2016-09-01 criteria provided, single submitter clinical testing
Invitae RCV000684774 SCV000543569 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-12-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg497Profs*6) 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 individuals affected with Lynch syndrome or Lynch syndrome associated cancers (PMID: 8872463, 12810663, 23695190, 22691310, 24323032, 15849733, 18566915, 15926618, 1756143, 21598002, 26053027). ClinVar contains an entry for this variant (Variation ID: 89753). Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075227 SCV000592407 pathogenic Lynch syndrome 2016-03-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000201993 SCV000601357 pathogenic not provided 2016-02-04 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000412044 SCV001251424 pathogenic Lynch syndrome II 2019-10-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001192571 SCV001360798 pathogenic Hereditary nonpolyposis colon cancer 2019-03-26 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1489dupC (p.Arg497ProfsX6) 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 277234 control chromosomes (gnomAD). c.1489dupC has been reported in the literature in multiple individuals affected with Lynch Syndrome (Kamiza_2015, Kurzawski_2006, Kondo_2003). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated that there was no interaction between the predicted truncated protein and PMS2 (Kondo_2003). Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000201993 SCV000257052 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.