Germline MLH1 c.-42 C > T is a likely pathogenic variant predisposing to a reduced-penetrance/modified Lynch syndrome phenotype featuring MLH1-methylated cancers

Abstract

The germline MLH1 c.-42 C > T (rs41285097) promoter variant has been identified in cases with MLH1-deficient colorectal or endometrial cancers but remains a variant of uncertain significance. Genetic testing identified two new MLH1 c.-42 C > T index cases from Australia and the USA. Clinicopathologic and molecular characterisation of tumour and non-neoplastic tissues was performed to investigate the potential mechanism of pathogenesis of this variant. The male Australian proband developed MLH1-deficient, BRAF p.V600 wildtype, CIMP-negative colon cancer at 61 years. MLH1 monoallelic methylation and a somatic pathogenic mutation, MLH1 c.1122_1126dup p.Asp376Valfs*27, were identified in his tum..