title: Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene.
abstract: Germline mutations in a number of genes involved in the recombinational repair of DNA double-strand breaks are associated with predisposition to breast and ovarian cancer. RAD51C is essential for homologous recombination repair, and a biallelic missense mutation can cause a Fanconi anemia-like phenotype. In index cases from 1,100 German families with gynecological malignancies, we identified six monoallelic pathogenic mutations in RAD51C that confer an increased risk for breast and ovarian cancer. These include two frameshift-causing insertions, two splice-site mutations and two nonfunctional missense mutations. The mutations were found exclusively within 480 pedigrees with the occurrence of both breast and ovarian tumors (BC/OC; 1.3%) and not in 620 pedigrees with breast cancer only or in 2,912 healthy German controls. These results provide the first unambiguous evidence of highly penetrant mutations associated with human cancer in a RAD51 paralog and support the 'common disease, rare allele' hypothesis.
authors.affiliation: Department of Obstetrics and Gynecology, Division of Tumor Genetics, Klinikum rechts der Isar der Technischen Universitaet Muenchen, Munich, Germany. alfons.meindl@lrz.tu-muenchen.de
authors.forename: Alfons
authors.initials: A
authors.lastname: Meindl
authors.forename: Heide
authors.initials: H
authors.lastname: Hellebrand
authors.forename: Constanze
authors.initials: C
authors.lastname: Wiek
authors.forename: Verena
authors.initials: V
authors.lastname: Erven
authors.forename: Barbara
authors.initials: B
authors.lastname: Wappenschmidt
authors.forename: Dieter
authors.initials: D
authors.lastname: Niederacher
authors.forename: Marcel
authors.initials: M
authors.lastname: Freund
authors.forename: Peter
authors.initials: P
authors.lastname: Lichtner
authors.forename: Linda
authors.initials: L
authors.lastname: Hartmann
authors.forename: Heiner
authors.initials: H
authors.lastname: Schaal
authors.forename: Juliane
authors.initials: J
authors.lastname: Ramser
authors.forename: Ellen
authors.initials: E
authors.lastname: Honisch
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
authors.forename: Hans E
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Karin
authors.initials: K
authors.lastname: Kast
authors.forename: Helmut
authors.initials: H
authors.lastname: Deissler
authors.forename: Christoph
authors.initials: C
authors.lastname: Engel
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.forename: Kornelia
authors.initials: K
authors.lastname: Neveling
authors.forename: Marion
authors.initials: M
authors.lastname: Kiechle
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mathew
authors.forename: Detlev
authors.initials: D
authors.lastname: Schindler
authors.forename: Rita K
authors.initials: RK
authors.lastname: Schmutzler
authors.forename: Helmut
authors.initials: H
authors.lastname: Hanenberg
mesh_terms: D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics; D005199:Fanconi Anemia / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D005858:Germany; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype
chemical_list: D004268:DNA-Binding Proteins; C448305:RAD51C protein, human
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