Tumour progression involves the inactivation of tumour suppressor genes and the activation of proto-oncogenes. Inactivation of both copies of a tumour suppressor gene is required for carcinogenesis, while germline deletion or inactivation of one copy results in an increase in the risk of cancer and is responsible for many of the known hereditary cancer syndromes. In contrast, activation of only one copy of a proto-oncogene is required for carcinogenesis. Germline deletion or inactivation of one copy of a proto-oncogene halves the risk of activation at this locus. We propose that studies of high risk cancer patients will show such "null oncogene" mutations.