Lynch syndrome (LS), the most common hereditary colorectal cancer syndrome, is caused by germline mutations in mismatch repair genes. Borràs and collaborators assessed the pathogenicity of variants of unknown significance detected in the mutational analysis of PMS2 gene using a comprehensive strategy. Pathogenic PMS2 mutations were detected in 9 of 13 (69%) candidate patients: seven alterations based on their molecular nature and two after demonstrating a functional defect. In all PMS2 mutations account for 6% of the LS cases. The comprehensive functional analysis performed has been useful in the classification of PMS2 VUS and contributes in refining the role of PMS2 in LS. (By Dr Gabriel Capellá and Dr Marta Pineda, http://jmg.bmj.com/content/early/2013/05/23/jmedgenet-2012-101511 )