Comprehensive analysis of the MLH1 promoter region in 480 colorectal cancer patients and 1,150 controls reveals new variants including one with a heritable constitutional MLH1 epimutation

Most MLH1 germline defects predisposing for Lynch Syndrome constitute sequence changes or deletions in the coding region.

Searching for variants in the MLH1 promoter causative for silencing or methylation, we sequenced the extended MLH1 promoter region for 480 colorectal cancer patients and 1,150 controls. We detected ten rare promoter variants. One was found in in a patient with constitutional MLH1 epimutation as disease causing mutation in the family, being the second heritable epimutation in MLH1 published so far.  Nine variants were not associated with methylation or allel silencing, pointing out that promoter variants are rarely conferring a hereditary MLH1 defect. (Dr. Monika Morak, )