Widespread resequencing for research and diagnostic purposes has disclosed a huge amount of genetic variability in the human genome, including the genes associated with inherited predisposition to colorectal cancer. The functional and clinical consequences of the gene variants identified are often difficult to predict. Therefore, it has becoming increasingly evident that standardized approaches for the clinical interpretation of gene variants are needed in order to maximize the clinical utility of molecular testing. In this chapter, we discuss strategies for variant classification, with special reference to hereditary colorectal cancer genes and to the functional and clinical points of evidence that are available for their interpretation.