title: Screening for a BRCA2 rearrangement in high-risk breast/ovarian cancer families: evidence for a founder effect and analysis of the associated phenotypes.
abstract: OBJECTIVE
  BRCA2 rearrangements are rare genetic events. A large BRCA2 genomic insertion was recurrently observed in our participants, and we sought to characterize it at the molecular and phenotypic level.
  
  
  METHODS
  We studied 210 high-risk breast/ovarian cancer families. Fifty-three probands were fully screened for BRCA1/2 mutations, and three of 53 had a large insertion in exon 3 of BRCA2. This finding was analyzed by polymerase chain reaction (PCR), reverse transcriptase PCR (RT-PCR), and sequencing. An additional 157 consecutive families were screened for this mutation by a three-step PCR method. Phenotype and haplotype analysis was also performed.
  
  
  RESULTS
  Sixteen BRCA mutations were observed in 19 of 53 patients (36% detection rate). A recurrent Alu motif insertion in position c.156_157 was observed after sequencing of an abnormal fragment obtained after the amplification of BRCA2 exon 3. RT-PCR revealed exon 3 skipping. Screening of this rearrangement identified 14 additional families (out of 157). In total, 17 (8%) of 210 high-risk families ascertained in our clinic were positive for this mutation. Segregation of a common haplotype (from D13S260 to D13S1695) confirmed a common origin, estimated to have occurred 2,400 to 2,600 years ago. The following four cancer phenotypes were observed in the 17 positive families: female breast (n = 9), male breast (n = 4), breast/ovarian (n = 2), and heterogeneous (n = 2). Male breast cancer was more frequently observed in c.156_157insAlu-positive families compared with negative families (23% v 12%, respectively), and 33% of all male breast cancer families with an identified BRCA mutation were c.156_157insAlu positive.
  
  
  CONCLUSIONS
  c.156_157insAlu is a founder mutation of Portuguese origin and is the most frequent BRCA2 rearrangement described to date.
authors.affiliation: Molecular Biology Department and Breast Cancer Risk Evaluation Clinic, Instituto Português de Oncologia de Lisboa, Francisco Gentil, Lisboa, Portugal.
authors.forename: Patrícia M
authors.initials: PM
authors.lastname: Machado
authors.forename: Rita D
authors.initials: RD
authors.lastname: Brandão
authors.forename: Branca M
authors.initials: BM
authors.lastname: Cavaco
authors.forename: Joana
authors.initials: J
authors.lastname: Eugénio
authors.forename: Sandra
authors.initials: S
authors.lastname: Bento
authors.forename: Mónica
authors.initials: M
authors.lastname: Nave
authors.forename: Paula
authors.initials: P
authors.lastname: Rodrigues
authors.forename: Aires
authors.initials: A
authors.lastname: Fernandes
authors.forename: Fátima
authors.initials: F
authors.lastname: Vaz
mesh_terms: D000328:Adult; D000368:Aged; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D018703:Founder Effect; D015321:Gene Rearrangement / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006801:Humans; D007585:Jews; D008297:Male; D008403:Mass Screening; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype
chemical_list: D024682:BRCA2 Protein