To date, many genetic changes have been described and reported in the cancer process. Since the first mutations were described, several attempts to establish genotype-phenotype correlations for these genetic alterations have been reported. Moreover, in vitro data have suggested effects of mutant proteins in proliferation. Genotype-phenotype correlations are not only important for predicting the clinical course of the disease and to allow tailor-made surveillance of individuals at risk, but also have implications for the elucidation of the molecular genetic mechanisms underlying genesis of cancer and the development of gene-based therapies. Here, we discuss genotype-phenotype correlation of cancer in mouse and man, and the functional aspects that may account for these observations important to both understand and treat the human disease process.