PALB2, a BRCA2-interacting protein, is identified as a breast cancer susceptibility gene. Biallelic mutations in PALB2 cause Fanconi anemia, similar to biallelic BRCA2 mutations. Monoallelic PALB2 mutations were found in 10/923 individuals with familial breast cancer, compared to 0/1,084 controls, indicating a 2.3-fold higher breast cancer risk. These mutations are associated with a higher risk of breast cancer, though the risk for male breast cancer may be higher than for female breast cancer. PALB2 mutations are linked to a 0.23% population attributable fraction for breast cancer. PALB2 is part of the Fanconi anemia-DNA repair pathway and is involved in BRCA2 functions. The study highlights the close relationship between Fanconi anemia and breast cancer predisposition. PALB2 mutations are not part of the Fanconi anemia core complex but act downstream of FANCD2. The study also shows that PALB2 mutations contribute to breast cancer risk, though less than BRCA2 mutations. Other genes like BRIP1 and CHEK2 also contribute to breast cancer risk, but their risks are lower than those of BRCA1, BRCA2, and TP53. The findings emphasize the complex relationship between breast cancer susceptibility and the Fanconi anemia-DNA repair pathway.PALB2, a BRCA2-interacting protein, is identified as a breast cancer susceptibility gene. Biallelic mutations in PALB2 cause Fanconi anemia, similar to biallelic BRCA2 mutations. Monoallelic PALB2 mutations were found in 10/923 individuals with familial breast cancer, compared to 0/1,084 controls, indicating a 2.3-fold higher breast cancer risk. These mutations are associated with a higher risk of breast cancer, though the risk for male breast cancer may be higher than for female breast cancer. PALB2 mutations are linked to a 0.23% population attributable fraction for breast cancer. PALB2 is part of the Fanconi anemia-DNA repair pathway and is involved in BRCA2 functions. The study highlights the close relationship between Fanconi anemia and breast cancer predisposition. PALB2 mutations are not part of the Fanconi anemia core complex but act downstream of FANCD2. The study also shows that PALB2 mutations contribute to breast cancer risk, though less than BRCA2 mutations. Other genes like BRIP1 and CHEK2 also contribute to breast cancer risk, but their risks are lower than those of BRCA1, BRCA2, and TP53. The findings emphasize the complex relationship between breast cancer susceptibility and the Fanconi anemia-DNA repair pathway.