Germline missense mutations in mismatch-repair genes and genetic testing for HNPCC

The clinical management of individuals in families with germline mutations in mismatch repair (MMR) genes relies not only on the accurate identification of genetic alterations but also on the interpretation of their pathogenicity. The spectrum of genetic alterations in MMR genes that predispose to hereditary nonpolyposis colorectal cancer (HNPCC) is very diverse. Of all mutations, it is the most difficult to predict the effect of missense mutations on the function of the protein. Therefore it is not always clear whether a missense mutation is pathogenic or just a harmless polymorphism. A number of computational and experimental assays (in vivo and in vitro) have been developed to assess the functional significance of mis-sense mutations in MMR genes. Despite the profusion of such assays, it is not clear that they are sufficiently sensitive and specific to serve as clinically applicable diagnostic tests for HNPCC.