title: BRCA1 and BRCA2 mutations in an Asian clinic-based population detected using a comprehensive strategy.
abstract: OBJECTIVE
  Genetic testing for germ line mutations in the BRCA1 and BRCA2 genes for some families at high risk for breast and/or ovarian cancer may yield negative results due to unidentified mutations or mutations with unknown clinical significance. We aimed to accurately determine the prevalence of mutations in these genes in an Asian clinic-based population by using a comprehensive testing strategy.
  
  
  METHODS
  Ninety-four subjects from 90 families were accrued from risk assessment clinics. In addition to conventional mutational screening of BRCA1 and BRCA2, multiplex ligation-dependent probe amplification for the detection of large genomic rearrangements, evaluation of splice site alterations using transcript analysis and SpliceSiteFinder prediction, and analysis of missense mutations of unknown significance by multiple sequence alignment, PolyPhen analysis, and comparison of Protein Data Bank structures were incorporated into our testing strategy.
  
  
  RESULTS
  The prevalence rates for clearly deleterious BRCA1 and BRCA2 mutations were 6.7% (6 of 90) and 8.9% (8 of 90), respectively, or 7.8% (7 of 90) and 11.1% (10 of 90), respectively, by including missense mutations predicted to be deleterious by computational analysis. In contrast to observations from European and American populations, deleterious mutations in BRCA2 (10 families) were more common than for BRCA1 (7 families). Overall, the frequency of mutations was 12.2% (n=11) by conventional screening. However, by including deleterious mutations detected using multiplex ligation-dependent probe amplification (n=1), transcript analysis (n=2), and computational evaluation of missense mutations (n=3), the frequency increased substantially to 18.9%. This suggests that the comprehensive strategy used is effective for identifying deleterious mutations in Asian individuals at high risk for breast and/or ovarian cancer.
authors.affiliation: Department of Medical Oncology, Division of Medical Sciences, National Cancer Center, Singapore 169610, Singapore.
authors.forename: Peter
authors.initials: P
authors.lastname: Ang
authors.forename: Irene H K
authors.initials: IH
authors.lastname: Lim
authors.forename: Tze-Chuen
authors.initials: TC
authors.lastname: Lee
authors.forename: Jie-Ting
authors.initials: JT
authors.lastname: Luo
authors.forename: Danny C T
authors.initials: DC
authors.lastname: Ong
authors.forename: Puay Hoon
authors.initials: PH
authors.lastname: Tan
authors.forename: Ann S G
authors.initials: AS
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010051:Ovarian Neoplasms / Q000235:genetics*