title: BRIP1, PALB2, and RAD51C mutation analysis reveals their relative importance as genetic susceptibility factors for breast cancer.
abstract: Mutations in the recognized breast cancer susceptibility genes BRCA1, BRCA2, TP53, ATM, and CHEK2 account for approximately 20% of hereditary breast cancer. This raises the possibility that mutations in other biologically relevant genes may be involved in genetic predisposition to breast cancer. In this study, BRIP1, PALB2, and RAD51C were sequenced for mutations as a result of previously 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 independent 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.
authors.affiliation: Discipline of Medical Genetics and Centre for Information-Based Medicine, The University of Newcastle, Hunter Medical Research Institute, John Hunter Hospital, Newcastle, NSW 2305, Australia.
authors.forename: Michelle W
authors.initials: MW
authors.lastname: Wong
authors.forename: Cecilia
authors.initials: C
authors.lastname: Nordfors
authors.forename: David
authors.initials: D
authors.lastname: Mossman
authors.forename: Gordana
authors.initials: G
authors.lastname: Pecenpetelovska
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Avery-Kiejda
authors.forename: Bente
authors.initials: B
authors.lastname: Talseth-Palmer
authors.forename: Nikola A
authors.initials: NA
authors.lastname: Bowden
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Scott
mesh_terms: D000328:Adult; D001315:Australia; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D000076164:Fanconi Anemia Complementation Group N Protein; D051856:Fanconi Anemia Complementation Group Proteins; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D020365:RNA Helicases / Q000235:genetics*; D017422:Sequence Analysis, DNA; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D000076164:Fanconi Anemia Complementation Group N Protein; D051856:Fanconi Anemia Complementation Group Proteins; D009687:Nuclear Proteins; C512790:PALB2 protein, human; C448305:RAD51C protein, human; D025521:Tumor Suppressor Proteins; C000618935:BRIP1 protein, human; D020365:RNA Helicases