BRIEF REPORT BRIP1, PALB2, and RAD51C mutation analysis reveals their relative importance as genetic susceptibility factors for breast cancer Michelle W. Wong • Cecilia Nordfors • David Mossman • Gordana Pecenpetelovska • Kelly A. Avery-Kiejda • Bente Talseth-Palmer • Nikola A. Bowden • Rodney J. Scott Received: 9 February 2011 / Accepted: 5 March 2011 / Published online: 16 March 2011 Ó Springer Science+Business Media, LLC. 2011 Abstract Mutations in the recognized breast cancer sus- ceptibility genes BRCA1, BRCA2, TP53, ATM, and CHEK2 account for approximately 20% of hereditary breast cancer. This raises the possibility that mutations in other biologi- cally relevant genes may be involved in genetic predispo- sition to breast cancer. In this study, BRIP1, PALB2, and RAD51C were sequenced for mutations as a result of pre- viously being associated with breast cancer risk due to their role in the double-strand break repair pathway and their close association with BRCA1 and BRCA2. Two truncating mutations in PALB2 (Q66X and W1038X), one of which is has not been reported before, were detected in an inde- pendent Australian cohort of 70 individuals with breast or ovarian cancer, and have strong family histories of breast or breast/ovarian cancer. In addition, six missense variants predicted to be causative were detected, one in BRIP1 and five in PALB2. No causative variants were identified in RAD51C. This study supports recent observations that although rare, PALB2 mutations are present in a small but substantial proportion of inherited breast cancer cases, and indicates that RAD51C at a population level does not account for a substantial number of familial breast cancer cases. Keywords Hereditary breast cancer  BRIP1  PALB2  RAD51C  Germline mutations Abbreviations AML Acute myeloid leukemia FA Fanconi anemia MLPA Multiplex ligation-dependent probe amplification PCR Polymerase chain reaction SNP Single nucleotide polymorphism Introduction Hereditary breast cancer was first described three decades ago and is characterized by a familial association of breast and/or ovarian cancer that occurs at unusually young ages and is often bilateral [1–3]. It is frequently associated with the presence of a strong family history, which remains the most important predisposing factor for breast cancer development [4, 5]. Three highly penetrant genes BRCA1, BRCA2, and TP53 are known to predispose to hereditary breast cancer [1]. In addition, other susceptibility genes have been identified that confer an increased risk of breast cancer that includes PTEN, CHK2, and ATM. A large proportion of breast cancer susceptibility genes identified to date are important components of the DNA damage response pathway [6]; yet, mutations in these genes com- bined only contribute to approximately 20% of all heredi- tary breast cancer cases [6–9] leaving the remaining 80% without a genetic diagnosis. M. W. Wong  D. Mossman  K. A. Avery-Kiejda  B. Talseth-Palmer  N. A. Bowden  R. J. Scott Discipline of Medical Genetics and Centre for Information- Based Medicine (CIBM), The University of Newcastle, Hunter Medical Research Institute (HMRI), John Hunter Hospital, Newcastle, NSW 2305, Australia C. Nordfors Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Solna (L1:00), 171 76 Stockholm, Sweden G. Pecenpetelovska  R. J. Scott (&) Division of Genetics, Hunter Area Pathology Service (HAPS), John Hunter Hospital, Lookout Road, New Lambton Heights, Newcastle, NSW 2305, Australia e-mail: rodney.scott@newcastle.edu.au 123 Breast Cancer Res Treat (2011) 127:853–859 DOI 10.1007/s10549-011-1443-0