Functional Analyses Help to Assess the Pathogenicity of MMR Gene Variants of Uncertain Significance

Abstract

Knowing that inherited defects in mismatch repair (MMR) genes predispose to Lynch syndrome (LS), the identification of these mutations in suspected LS families is of prime importance. However, a major problem in the diagnosis and management of LS is the frequent occurrence of variants of uncertain significance (VUS) in the MMR genes. The consequence of a non-truncating mutation can vary from none to complete dysfunction of the protein. Thus, functional assessment by investigating how a non-truncating mutation affects the quantity and biochemical behaviour of the protein variant as compared to the wild-type protein has been shown to be an efficient manner to determine the pathogenicity of MMR gene variations. Furthermore, a stepwise assessment model emphasizing the use of family history and tumour pathological data to guide during the assessment process has been applied. Overall, the model utilizes data from incompletely validated assays supplemented with data derived from other sources such as from in silico analyses to classify VUS for clinical purposes.