ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1459C>T (p.Arg487Ter) (rs63749795)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 11
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075218 SCV000106210 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Ambry Genetics RCV000128870 SCV000172727 pathogenic Hereditary cancer-predisposing syndrome 2018-12-29 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000524240 SCV000253786 pathogenic Hereditary nonpolyposis colon cancer 2018-12-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg487*) 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 observed in several individuals and families affected with colorectal cancer and Lynch syndrome (PMID: 10713887, 14635101, 15849733, 15870828, 21636617, 21681552, 24344984). ClinVar contains an entry for this variant (Variation ID: 89744). Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000255034 SCV000321897 pathogenic not provided 2017-01-10 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1459C>T at the cDNA level and p.Arg487Ter (R487X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), 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 individuals with suspected Lynch syndrome (Lee 2005, Mangold 2005, Win 2011, Serrano 2012, De Lellis 2013, Lagerstedt-Robinson 2016) and is considered pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075218 SCV000592406 pathogenic Lynch syndrome 2014-08-01 criteria provided, single submitter clinical testing
Color RCV000128870 SCV000684746 pathogenic Hereditary cancer-predisposing syndrome 2016-12-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000075218 SCV000696112 pathogenic Lynch syndrome 2016-07-20 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1459C>T (p.Arg487X) variant results in a premature termination codon, predicted to cause a truncated or absent MLH1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was not found in controls (ExAC, 1000 Gs or ESP) and has been reported in multiple affected individuals via publications. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
Counsyl RCV000662808 SCV000785641 pathogenic Lynch syndrome II 2017-10-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763103 SCV000893645 pathogenic Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000075218 SCV000914321 pathogenic Lynch syndrome 2019-01-30 criteria provided, single submitter research
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000255034 SCV000691862 pathogenic not provided no assertion criteria provided clinical testing

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.