title: RAD51 and breast cancer susceptibility: no evidence for rare variant association in the Breast Cancer Family Registry study.
abstract: BACKGROUND
  Although inherited breast cancer has been associated with germline mutations in genes that are functionally involved in the DNA homologous recombination repair (HRR) pathway, including BRCA1, BRCA2, TP53, ATM, BRIP1, CHEK2 and PALB2, about 70% of breast cancer heritability remains unexplained. Because of their critical functions in maintaining genome integrity and already well-established associations with breast cancer susceptibility, it is likely that additional genes involved in the HRR pathway harbor sequence variants associated with increased risk of breast cancer. RAD51 plays a central biological function in DNA repair and despite the fact that rare, likely dysfunctional variants in three of its five paralogs, RAD51C, RAD51D, and XRCC2, have been associated with breast and/or ovarian cancer risk, no population-based case-control mutation screening data are available for the RAD51 gene. We thus postulated that RAD51 could harbor rare germline mutations that confer increased risk of breast cancer.
  
  
  RESULTS
  We screened the coding exons and proximal splice junction regions of the gene for germline sequence variation in 1,330 early-onset breast cancer cases and 1,123 controls from the Breast Cancer Family Registry, using the same population-based sampling and analytical strategy that we developed for assessment of rare sequence variants in ATM and CHEK2. In total, 12 distinct very rare or private variants were characterized in RAD51, with 10 cases (0.75%) and 9 controls (0.80%) carrying such a variant. Variants were either likely neutral missense substitutions (3), silent substitutions (4) or non-coding substitutions (5) that were predicted to have little effect on efficiency of the splicing machinery.
  
  
  CONCLUSIONS
  Altogether, our data suggest that RAD51 tolerates so little dysfunctional sequence variation that rare variants in the gene contribute little, if anything, to breast cancer susceptibility.
authors.affiliation: Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Le Calvez-Kelm
authors.forename: Javier
authors.initials: J
authors.lastname: Oliver
authors.forename: Francesca
authors.initials: F
authors.lastname: Damiola
authors.forename: Nathalie
authors.initials: N
authors.lastname: Forey
authors.forename: Nivonirina
authors.initials: N
authors.lastname: Robinot
authors.forename: Geoffroy
authors.initials: G
authors.lastname: Durand
authors.forename: Catherine
authors.initials: C
authors.lastname: Voegele
authors.forename: Maxime P
authors.initials: MP
authors.lastname: Vallée
authors.forename: Graham
authors.initials: G
authors.lastname: Byrnes
authors.forename: Breast Cancer Family
authors.initials: BC
authors.lastname: Registry
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
authors.forename: Irene L
authors.initials: IL
authors.lastname: Andrulis
authors.forename: Esther M
authors.initials: EM
authors.lastname: John
authors.forename: Sean V
authors.initials: SV
authors.lastname: Tavtigian
authors.forename: Fabienne
authors.initials: F
authors.lastname: Lesueur
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D051135:Rad51 Recombinase / Q000235:genetics*; D012042:Registries
chemical_list: D051135:Rad51 Recombinase