Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene.
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.
Meindl
Alfons
A
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
Hellebrand
Heide
H
Wiek
Constanze
C
Erven
Verena
V
Wappenschmidt
Barbara
B
Niederacher
Dieter
D
Freund
Marcel
M
Lichtner
Peter
P
Hartmann
Linda
L
Schaal
Heiner
H
Ramser
Juliane
J
Honisch
Ellen
E
Kubisch
Christian
C
Wichmann
Hans E
HE
Kast
Karin
K
Deissler
Helmut
H
Engel
Christoph
C
Müller-Myhsok
Bertram
B
Neveling
Kornelia
K
Kiechle
Marion
M
Mathew
Christopher G
CG
Schindler
Detlev
D
Schmutzler
Rita K
RK
Hanenberg
Helmut
H
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
D004268:DNA-Binding Proteins; C448305:RAD51C protein, human
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