title: Increased rate of phenocopies in all age groups in BRCA1/BRCA2 mutation kindred, but increased prospective breast cancer risk is confined to BRCA2 mutation carriers.
abstract: BACKGROUND
  To establish, if among unaffected noncarrier relatives in a family with an established BRCA1/2 mutation, there is an increased risk of breast cancer.
  
  
  METHODS
  We identified 49 women with breast cancer who were first-degree relatives of a pathogenic mutation carrier among 807 BRCA1/2 families but who tested negative for the specific mutation. A prospective analysis of breast cancer from date of family ascertainment was performed for first-degree relatives of proven BRCA1/2 mutation carriers and compared with population-expected incidence rates.
  
  
  RESULTS
  Women who prospectively test negative for BRCA1/2 mutations showed excess risk of breast cancer to be confined to BRCA2 noncarriers with an observed:expected (O/E) ratio of 4.57 [95% confidence interval (CI) 2.50-7.67; P < 0.0001; O/E in BRCA1 noncarriers, 1.77]; this dropped to 2.01 for BRCA2 [relative risk (RR), 1.99; 95% CI, 0.54-5.10] from date of predictive test. Genotyping of 18 breast cancer susceptibility single-nucleotide polymorphisms (SNP) defined an RR of 1.31 for BRCA2 breast cancer phenocopies with a breast cancer diagnosis at age less than 60 years.
  
  
  CONCLUSIONS
  Noncarriers remain at risk in the prospective follow-up of women who tested negative for BRCA1/2. Women testing negative in BRCA2 families may have increased risk of breast cancer compared with population levels, particularly with strong breast cancer history in close relatives. Any increased risk in BRCA1 families is likely to be insufficient to recommend additional interventions.
  
  
  CONCLUSIONS
  Our work can help with counseling women from BRCA1/2 families who have tested negative, and could impact on how individual breast cancer risk is related back to these women.
authors.affiliation: Authors' Affiliations: Department of Genetic Medicine, The University of Manchester, Manchester Academic Health Science Centre, St. Mary's Hospital; Genesis Prevention Centre, University Hospital of South Manchester Southmoor Road; Centre for Health Informatics, Institute of Population Health, The University of Manchester, Manchester; and Centre for Rare Diseases and Personalised Medicine, School of Clinical and Experimental Medicine, University of Birmingham College of Medical and Dental Sciences, and West Midlands Regional Genetics Service, Birmingham, United Kingdom.
authors.forename: D Gareth R
authors.initials: DG
authors.lastname: Evans
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Ingham
authors.forename: Iain
authors.initials: I
authors.lastname: Buchan
authors.forename: Emma R
authors.initials: ER
authors.lastname: Woodward
authors.forename: Helen
authors.initials: H
authors.lastname: Byers
authors.forename: Anthony
authors.initials: A
authors.lastname: Howell
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
authors.forename: William G
authors.initials: WG
authors.lastname: Newman
authors.forename: Fiona
authors.initials: F
authors.lastname: Lalloo
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors