Women with a family history of breast cancer have mutations in one of the breast cancer susceptibility genes, BRCA1 or BRCA2. Since the discovery of these two genes, around 100,000 women worldwide have undergone genetic testing. The decisions they make based on the results are usually life changing and may involve radical preventive surgeries such as prophylactic mastectomy and oophorectamy. However, not all mutations will lead to breast cancer, and to prevent unnecessary surgery, we are developing assays to determine which mutations adversely affect the functions of the protein encoded by the BRCA1 gene. The functions of BRCA1 are mediated by numerous interactions that are required for cell-cycle and centrosome control, transcriptional regulation and the DNA damage response. Missense mutations that perturb the interactions of BRCA1 will adversely affect these functions and are, therefore, likely to lead to breast cancer. Determining the effect missense mutations have on the interaction of BRCA1 with DNA will form the basis of the assay described in this chapter.