ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.-7C>T (rs104894994)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000776038 SCV000910640 benign Hereditary cancer-predisposing syndrome 2015-11-17 criteria provided, single submitter clinical testing
GeneDx RCV000114845 SCV000149357 uncertain significance not provided 2018-11-09 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.-7C>T, and describes a nucleotide substitution 7 base pairs upstream of the MLH1 ATG translational start site in the 5' untranslated region (UTR). The surrounding sequence, with the base that is substituted in brackets, is CTGG[C/T]GCCA. According to the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) database, MLH1 c.-7C>T is an uncertain variant based on insufficient evidence and has been reported to co-occur with MLH1 c.-28A>G in individuals with a personal and/or family history suggestive of Lynch syndrome, as well as in a hereditary prostate cancer family (Fredriksson 2006, Thompson 2014, Hesson 2015, Lagerstedt-Robinson 2016). In one study of two such individuals from suspected Lynch syndrome families, these variants conferred an approximate 50% reduction in MLH1 expression, although there was no MLH1 promoter methylation and the promoter remained epigenetically unaltered (Hesson 2015). MLH1 c.-7C>T has also been reported with MLH1 c.-28A>G in individuals with colon cancer whose tumors were reportedly not suggestive of Lynch syndrome (Morak 2018). Although this variant does not appear to affect the start codon or the Kozak translational consensus sequence, constitutional epigenetic silencing of MLH1 has been suggested as an alternate mechanism responsible for Lynch syndrome and variants located within the 5?UTR have been shown to result in allele-specific promoter methylation and subsequent transcriptional silencing (Hitchins 2011, Ward 2013). This variant was observed at an allele frequency of 0.80% (207/25788) in individuals of Finnish ancestry in large population cohorts (Lek 2016). At this time, we consider MLH1 c.-7C>T to be a variant of uncertain significance.
Harris Lab, University of Minnesota RCV000114845 SCV000148740 not provided not provided no assertion provided not provided
Invitae RCV000075068 SCV000259816 benign Lynch syndrome 2016-02-17 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000115448 SCV000691840 uncertain significance not specified 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.