ClinVar

Description

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). 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 0.88% (56/6,614) in individuals of Finnish ancestry in large population cohorts and the base that is altered is conserved through mammals (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). At this time, we consider MLH1 c.-7C>T to be a variant of uncertain significance.