Variation in cancer risks, by mutation position, in BRCA2 mutation carriers

Am J Hum Genet. 2001 Feb;68(2):410-9. doi: 10.1086/318181. Epub 2001 Jan 19.


Cancer occurrence in 164 families with breast/ovarian cancer and germline BRCA2 mutations was studied to evaluate the evidence for genotype-phenotype correlations. Mutations in a central portion of the gene (the "ovarian cancer cluster region" [OCCR]) were associated with a significantly higher ratio of cases of ovarian:breast cancer in female carriers than were mutations 5' or 3' of this region (P<.0001), extending previous observations. The optimal definition of the OCCR, as judged on the basis of deviance statistics, was bounded by nucleotides 3059-4075 and 6503-6629. The relative and absolute risks of breast and ovarian cancer associated with OCCR and non-OCCR mutations were estimated by a conditional likelihood approach, conditioning on the set of mutations observed in the families. OCCR mutations were associated both with a highly significantly lower risk of breast cancer (relative risk [RR] 0.63; 95% confidence interval (95% CI) 0.46-0.84; P=.0012) and with a significantly higher risk of ovarian cancer (RR = 1.88; 95% CI = 1.08-3.33; P=.026). No other differences in breast or ovarian cancer risk, by mutation position, were apparent. There was some evidence for a lower risk of prostate cancer in carriers of an OCCR mutation (RR = 0.52; 95% CI = 0.24-1.00; P=.05), but there was no evidence of a difference in breast cancer risk in males. By age 80 years, the cumulative risk of breast cancer in male carriers of a BRCA2 mutation was estimated as 6.92% (95% CI = 1.20%-38.57%). Possible mechanisms for the variation in cancer risk are suggested by the coincidence of the OCCR with the RAD51-binding domain.

Publication types

  • Comparative Study
  • Multicenter Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Age Factors
  • Aged
  • BRCA2 Protein
  • Breast Neoplasms / genetics
  • Breast Neoplasms, Male / genetics
  • Family Health
  • Female
  • Genetic Variation
  • Heterozygote*
  • Humans
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutation
  • Neoplasm Proteins / genetics*
  • Neoplasms / genetics*
  • Ovarian Neoplasms / genetics
  • Prostatic Neoplasms / genetics
  • Risk Factors
  • Statistics as Topic
  • Transcription Factors / genetics*


  • BRCA2 Protein
  • Neoplasm Proteins
  • Transcription Factors

Associated data

  • OMIM/600185