RAD51 135G-->C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies.

Antonis C Antoniou, Olga M Sinilnikova, Jacques Simard, Mélanie Léoné, Martine Dumont, Susan L Neuhausen, Jeffery P Struewing, Dominique Stoppa-Lyonnet, Laure Barjhoux, David J Hughes, Isabelle Coupier, Muriel Belotti, Christine Lasset, Valérie Bonadona, Yves-Jean Bignon, Timothy R Rebbeck, Theresa Wagner, Henry T Lynch, Susan M Domchek, Katherine L NathansonJudy E Garber, Jeffrey Weitzel, Steven A Narod, Gail Tomlinson, Olufunmilayo I Olopade, Andrew Godwin, Claudine Isaacs, Anna Jakubowska, Jan Lubinski, Jacek Gronwald, Bohdan Górski, Tomasz Byrski, Tomasz Huzarski, Susan Peock, Margaret Cook, Caroline Baynes, Alexandra Murray, Mark Rogers, Peter A Daly, Huw Dorkins, Rita K Schmutzler, Beatrix Versmold, Christoph Engel, Alfons Meindl, Norbert Arnold, Dieter Niederacher, Helmut Deissler, Amanda B Spurdle, Xiaoqing Chen, Nicola Waddell, Nicole Cloonan, Tomas Kirchhoff, Kenneth Offit, Eitan Friedman, Bella Kaufmann, Yael Laitman, Gilli Galore, Gad Rennert, Flavio Lejbkowicz, Leon Raskin, Irene L Andrulis, Eduard Ilyushik, Hilmi Ozcelik, Peter Devilee, Maaike P G Vreeswijk, Mark H Greene, Sheila A Prindiville, Ana Osorio, Javier Benitez, Michal Zikan, Csilla I Szabo, Outi Kilpivaara, Heli Nevanlinna, Ute Hamann, Francine Durocher, Adalgeir Arason, Fergus J Couch, Douglas F Easton, Georgia Chenevix-Trench

Research output: Contribution to journalArticlepeer-review


RAD51 is an important component of double-stranded DNA-repair mechanisms that interacts with both BRCA1 and BRCA2. A single-nucleotide polymorphism (SNP) in the 5' untranslated region (UTR) of RAD51, 135G-->C, has been suggested as a possible modifier of breast cancer risk in BRCA1 and BRCA2 mutation carriers. We pooled genotype data for 8,512 female mutation carriers from 19 studies for the RAD51 135G-->C SNP. We found evidence of an increased breast cancer risk in CC homozygotes (hazard ratio [HR] 1.92 [95% confidence interval {CI} 1.25-2.94) but not in heterozygotes (HR 0.95 [95% CI 0.83-1.07]; P=.002, by heterogeneity test with 2 degrees of freedom [df]). When BRCA1 and BRCA2 mutation carriers were analyzed separately, the increased risk was statistically significant only among BRCA2 mutation carriers, in whom we observed HRs of 1.17 (95% CI 0.91-1.51) among heterozygotes and 3.18 (95% CI 1.39-7.27) among rare homozygotes (P=.0007, by heterogeneity test with 2 df). In addition, we determined that the 135G-->C variant affects RAD51 splicing within the 5' UTR. Thus, 135G-->C may modify the risk of breast cancer in BRCA2 mutation carriers by altering the expression of RAD51. RAD51 is the first gene to be reliably identified as a modifier of risk among BRCA1/2 mutation carriers.
Original languageEnglish
JournalAmerican Journal of Human Genetics
Publication statusPublished - 1 Dec 2007

Other keywords

  • Adolescent
  • Adult
  • Alternative Splicing
  • BRCA1 Protein
  • BRCA2 Protein
  • Breast Neoplasms
  • DNA Primers
  • DNA Repair
  • Family
  • Female
  • Genetic Variation
  • Heterozygote
  • Homozygote
  • Humans
  • Middle Aged
  • Mutation
  • Polymorphism, Single Nucleotide
  • Rad51 Recombinase
  • Reverse Transcriptase Polymerase Chain Reaction


Dive into the research topics of 'RAD51 135G-->C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies.'. Together they form a unique fingerprint.

Cite this