Interpreting the clinical significance of mismatch repair gene sequence variants

Abstract

The clinical classification of inherited nucleotide sequence variants identified in disease-related genes has a direct impact on the clinical management of patients and their families. Lynch syndrome is an autosomal dominant cancer predisposition syndrome caused by germline mutations in the mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2). However, ~30% of MMR gene variants identified in suspected Lynch cases are of uncertain clinical significance, which constitutes a challenge for genetic counselling and clinical management of families. In the past there has been no uniform system to tackle these variants, and mainly ad hoc methods have been utilized to determine if they are disease causing. The multifactorial likelihood model approach was initially developed for the evaluation of sequence variants in the BRCA1/2 cancer predisposition genes. It was adapted for MMR gene variants to provide a quantitative measure of risk in the form of probability of pathogenicity. Estimates of prior probability of pathogenicity based on evolutionary sequence conservation and physicochemical characteristics of predicted alterations were combined with variant segregation information and tumour features. Microsatellite instability (MSI) and somatic BRAF V600E tumour data for unselected colorectal cancer probands of known pathogenic variant status were used to derive likelihood ratios (LR) for tumour characteristics using the Colon Cancer Family Registry resource.The LR in favour of pathogenicity was estimated to be ~12-fold for a MSI and BRAF V600E mutation-negative colorectal tumour. Our findings provide a working multifactorial likelihood model for classifications that carefully considers mode of ascertainment for gene testing.