To date, a large number of mutations have been screened from breast and ovarian cancer patients. However, most of them are classified into benign or unidentified alterations due to their undetectable phenotypes. Whether and how they could cause tumors remains unknown, and this significantly limits diagnosis and therapy. Here, in a study of a family with hereditary breast and ovarian cancer, we find that two BARD1 mutations, P24S and R378S, simultaneously exist in cis in surviving cancer patients. Neither of the single mutations causes a functional change, but together they synergetically impair the DNA damage response and lead to tumors in vitro and in vivo. Thus, our report not only demonstrates that BARD1 defects account for tumorigenesis but also uncovers the potential risk of synergetic effects between the large number of cis mutations in individual genes in the human genome.