To identify rare genetic variants that confer moderate risks of breast or ovarian cancer, Ruark et al. sequenced 507 genes encoding DNA repair proteins in peripheral blood lymphocytes from 1,150 patients with breast cancer, 69 of whom also had ovarian cancer. They identified protein-truncating variants in the p53-inducible protein phosphatase PPM1D that were associated with predisposition to breast and ovarian cancer, and then confirmed this in a case–control analysis of 13,642 individuals. Interestingly, these mutations were mosaic in lymphocyte DNA and were not present in tumour cells. The mutations did not block PPM1D function but led to the suppression of p53 following exposure to ionizing radiation.