title: Contribution of large genomic BRCA1 alterations to early-onset breast cancer selected for family history and tumour morphology: a report from The Breast Cancer Family Registry.
abstract: BACKGROUND
  Selecting women affected with breast cancer who are most likely to carry a germline mutation in BRCA1 and applying the most appropriate test methodology remains challenging for cancer genetics services. We sought to test the value of selecting women for BRCA1 mutation testing on the basis of family history and/or breast tumour morphology criteria as well as the value of testing for large genomic alterations in BRCA1.
  
  
  METHODS
  We studied women participating in the Breast Cancer Family Registry (BCFR), recruited via population-based sampling, who had been diagnosed with breast cancer before the age of 40 years who had a strong family history of breast or ovarian cancer (n = 187) and/or a first primary breast tumour with morphological features consistent with carrying a BRCA1 germline mutation (n = 133; 37 met both criteria). An additional 184 women diagnosed before the age of 40 years who had a strong family history of breast or ovarian cancer and who were not known to carry a germline BRCA1 mutation were selected from among women who had been recruited into the BCFR from clinical genetics services. These 467 women had been screened for BRCA1 germline mutations, and we expanded this testing to include a screen for large genomic BRCA1 alterations using Multiplex Ligation-dependent Probe Amplification.
  
  
  RESULTS
  Twelve large genomic BRCA1 alterations were identified, including 10 (4%) of the 283 women selected from among the population-based sample. In total, 18 (12%), 18 (19%) and 16 (43%) BRCA1 mutations were identified in the population-based groups selected on the basis of family history only (n = 150), the group selected on the basis of tumour morphology only (n = 96) and meeting both criteria (n = 37), respectively.
  
  
  CONCLUSIONS
  Large genomic alterations accounted for 19% of all BRCA1 mutations identified. This study emphasises the value of combining information about family history, age at diagnosis and tumour morphology when selecting women for germline BRCA1 mutation testing as well as including a screen for large genomic alterations.
authors.affiliation: Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Letitia D
authors.initials: LD
authors.lastname: Smith
authors.forename: Andrea A
authors.initials: AA
authors.lastname: Tesoriero
authors.forename: Ee M
authors.initials: EM
authors.lastname: Wong
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Ramus
authors.forename: Frances P
authors.initials: FP
authors.lastname: O'Malley
authors.forename: Anna Marie
authors.initials: AM
authors.lastname: Mulligan
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Terry
authors.forename: Ruby T
authors.initials: RT
authors.lastname: Senie
authors.forename: Regina M
authors.initials: RM
authors.lastname: Santella
authors.forename: Esther M
authors.initials: EM
authors.lastname: John
authors.forename: Irene L
authors.initials: IL
authors.lastname: Andrulis
authors.forename: Hilmi
authors.initials: H
authors.lastname: Ozcelik
authors.forename: Mary B
authors.initials: MB
authors.lastname: Daly
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
authors.forename: Saundra S
authors.initials: SS
authors.lastname: Buys
authors.forename: Stephen
authors.initials: S
authors.lastname: Fox
authors.forename: David E
authors.initials: DE
authors.lastname: Goldgar
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
mesh_terms: D000328:Adult; D017668:Age of Onset; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D012042:Registries