In this cost-effectiveness microsimulation modeling study incorporating data from 11 836 women, unselected BRCA1/BRCA2/PALB2 testing at breast cancer diagnosis was extremely cost-effective compared with BRCA1/BRCA2 testing based on clinical criteria or family history for UK and US health systems, with incremental cost-effectiveness ratios of £10 464 or £7216 and $65 661 or $61 618 per quality-adjusted life-year, respectively. This evidence concerns the gene BRCA2 and breast cancer.