Prevalence of pathogenic mismatch repair mutations in an Irish cohort after clinical and molecular pre-selection.

Abstract

574 Background: Lynch syndrome (LS) is a highly penetrant, autosomal dominant multi-system disorder characterised by an inherited predisposition to a range of cancers. LS is caused by germline mutations in one of the mismatch repair (MMR) genes ( MSH2, MLH1, MSH2 and PMS2). Tumours from patients with LS have characteristic features resulting from the underlying molecular involvement of defective MMR, that is, the presence of microsatellite instability (MSI) and the absence of MMR protein expression by immunohistochemistry (IHC) corresponding to the mutated gene. MMR mutations are identified in approximately 60% of microsatellite instability-high (MSI-H) cancer patients fulfilling clinical criteria for LS. We sought to define the prevalence of pathogenic MMR mutations among an Irish cohort following molecular pre-selection with IHC/MSI and BRAF/MLH1 hypermethylation testing Methods: The results of diagnostic MMR genetic screening conducted on individuals following genetic counselling, in the Clinical Cancer Genetics Departments of the Mater Campus between January 2011 to September 2016, were correlated with ages at diagnoses and genetic test result. Results: This clinic-based cohort of affected individuals (n = 35) consisted of 22 females and 13 males. Median age at first cancer diagnosis was 44 years, range 23 to 86, standard deviation 12.3. Deleterious mutations were identified in 16 patients (45.7%), 6 in MLH1, 3 in MSH2, 2 in MSH6 and 5 in PMS2. Thirteen patients had a normal genetics test result (37.1%). Variants of uncertain significance (VUS) were identified in 6 patients (17.1%). With additional molecular testing and co-segregation studies in one family an MLH1 VUS was reclassified as likely pathogenic, facilitating pre-symptomatic testing for family members. This reclassification gives a revised prevalence of pathogenic mutation in this cohort of 48.5% and a VUS detection rate of 14.2%. Conclusions: We report a higher than expected VUS rate following molecular preselection of patients likely to have LS. No mutations were identified in 37% of patients supporting the presence of alternative negative regulators of the MMR pathway.