ClinVar

Description

This variant is denoted MLH1 c.-33T>G, and describes a nucleotide substitution 33 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 AGCA[T/G]CTAG. MLH1 c.-33T>G was identified along with a pathogenic MSH2 variant in an individual with an MSI-high colorectal cancer with absent expression of the MSH2 and MSH6 proteins (Hampel 2008). Of note, constitutional epigenetic silencing of MLH1 has been suggested as an alternate mechanism responsible for Lynch syndrome, and variants located within the MLH1 5' UTR have been shown to result in allele specific promoter methylation and subsequent transcriptional silencing (Hitchins 2009, Ward 2013). MLH1 c.-33T>G was not observed at a significant allele frequency in large population cohorts (Lek 2016). The thymine (T) nucleotide that is altered is not conserved. Based on currently available evidence, we consider MLH1 c.-33T>G to be a variant of uncertain significance.