Partner and localizer of BRCA2 (PALB2), plays an important functional role in DNA damage repair. Recent studies indicate that germline mutations in PALB2 predispose individuals to a high risk of developing familial breast cancer. Therefore, comprehensive identification of PALB2 germline mutations is potentially important for understanding their roles in tumorigenesis and for testing their potential utility as clinical targets. Most of the previous studies of PALB2 have focused on familial breast cancer cases with normal/wild-type BRCA1 and BRCA2 (BRCAx). We hypothesize that PALB2 genetic mutations also exist in individuals with BRCA mutations (BRCA?). To test this hypothesis, PALB2 germline mutations were screened in 107 exome data sets collected from familial breast cancer families who were either BRCA1? or BRCAx. Two novel heterozygous mutations predicted to alter the function of PALB2 were identified (c.2014G[C, p.E672Q and c.2993G[A, p.G998E). Notably, both of these mutations co-existed in BRCA1? and BRCA1x families. These studies show that mutations in PALB2 can occur independent of the status of BRCA1 mutations, and they highlight the importance to include BRCA1? families in PALB2 mutation screens.