Overview of the Genetic Aspects of Lynch Syndrome

Lynch syndrome (LS) is one of the most common inherited cancer predisposition syndromes and the most important cause of hereditary colorectal and endometrial cancers. It is inherited in an autosomal dominant pattern, caused by a pathogenic germline variant in one of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2), which encode proteins responsible for maintaining genome stability. A defective MMR system confers an elevated risk of developing certain types of cancer, at a younger age than in the general population and at a high rate of multiple primary neoplasia. Lynch syndrome is not just one disease, but a collection of different subtypes of underlying molecular aspects with specific clinical implications. A better understanding of these subgroup profiles could offer better care for each patient, leading to more personalized risk-reduction and surveillance strategies. Lynch syndrome is a frequent but yet underdiagnosed condition that needs multidisciplinary increased awareness for correct diagnosis and management. The aim of this review is to provide a summary of available literature data on the genetic aspects of Lynch syndrome together with geno-type-phenotype correlations and its clinical implications in the detection, genetic counseling, genetic testing, risk stratification, and management of this condition.