Using colorectal cancer (CRC) as an example, we present the hypothesis that quantitative immunoassays for wild-type (full-length) proteins can be used to identify carriers of traits for hereditary diseases. In the case of hereditary CRC, this involves identifying individuals with germline mutations in a mismatch-repair (MMR) gene (mainly hMSH2 or hMLH1) or in the adenomatous polyposis coli (APC) gene. Because expression of wild-type protein should reflect wild-type gene dosage, we predicted that individuals harboring a germline mutation will have a reduction of approximately 50% in expression in lymphocytes of the corresponding full-length protein. In this pilot study, we tested lymphoblastoid cell lines that had been established from controls and individuals with, or at high risk for, hereditary CRC: 9 lines from healthy, unaffected individuals; 4 from affected members in familial adenomatous polyposis families (with known germ-line APC mutation); 42 from CRC patients in our Familial CRC Registry (increased risk of hereditary nonpolyposis colon cancer as assessed by family history, age at adenoma or carcinoma diagnosis, and other clinical criteria). For MSH2 and MLH1 we used western blots; for APC we used immunoprecipitation. All familial adenomatous polyposis lines had about 50% less immunoprecipitable full-length APC protein. Some cell lines (7 of 42) from Familial CRC Registry patients showed on western blots a reduction (mean 46%) in either MSH2 or MLH1 (relative to the other protein). All 7 subsequently were proved to contain a germline MMR mutation. We conclude that (1) because most of the expected CRC-causing germ line mutations are truncation-causing, immunoassays for wild-type protein should be able to identify most individuals with hereditary CRC-causing traits; (2) these assays, which are more practical and inexpensive than current mutation-detecting tests for hereditary CRC traits, have the potential for commercial development into broad-based population screens of high-risk patients and their families and the potential to save both lives and health-care dollars; (3) this strategy may be useful for other hereditary cancers and even other hereditary diseases; (4) our approach has the potential to greatly benefit public-health programs for cancer control.