Germ line p53 mutations represent a genetic predisposition for cancer development. At the present time, their detection requires extensive work and their functional significance must be documented. Therefore, we have designed a simple biological assay which detects functionally significant germ line p53 mutations. This assay is based on the cloning of the patient's p53 complementary DNA into a eukaryotic expression vector followed by the cotransfection into human cells of the recombinant vector with a reporter plasmid for the transcriptional activity of p53. This assay potentially offers a powerful method to screen fibroblasts or lymphocytes from patients for germ line mutations which inactivate the p53 tumor suppressor gene.