title: BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes.
abstract: OBJECTIVE
  To compare genetic test results for deleterious mutations of BRCA1 and BRCA2 with estimated probabilities of carrying such mutations; to assess sensitivity of genetic testing; and to assess the relevance of other susceptibility genes in familial breast and ovarian cancer.
  
  
  METHODS
  Data analyzed were from six high-risk genetic counseling clinics and concern individuals from families for which at least one member was tested for mutations at BRCA1 and BRCA2. Predictions of genetic predisposition to breast and ovarian cancer for 301 individuals were made using BRCAPRO, a statistical model and software using Mendelian genetics and Bayesian updating. Model predictions were compared with the results of genetic testing.
  
  
  RESULTS
  Among the test individuals, 126 were Ashkenazi Jewish, three were male subjects, 243 had breast cancer, 49 had ovarian cancer, 34 were unaffected, and 139 tested positive for BRCA1 mutations and 29 for BRCA2 mutations. BRCAPRO performed well: for the 150 probands with the smallest BRCAPRO carrier probabilities (average, 29.0%), the proportion testing positive was 32.7%; for the 151 probands with the largest carrier probabilities (average, 95.2%), 78.8% tested positive. Genetic testing sensitivity was estimated to be at least 85%, with false-negatives including mutations of susceptibility genes heretofore unknown.
  
  
  CONCLUSIONS
  BRCAPRO is an accurate counseling tool for determining the probability of carrying mutations of BRCA1 and BRCA2. Genetic testing for BRCA1 and BRCA2 is highly sensitive, missing an estimated 15% of mutations. In the populations studied, breast cancer susceptibility genes other than BRCA1 and BRCA2 either do not exist, are rare, or are associated with low disease penetrance.
authors.affiliation: Department of Biostatistics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030-4009, USA. dberry@mdanderson.org
authors.forename: Donald A
authors.initials: DA
authors.lastname: Berry
authors.forename: Edwin S
authors.initials: ES
authors.lastname: Iversen
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Gudbjartsson
authors.forename: Elaine H
authors.initials: EH
authors.lastname: Hiller
authors.forename: Judy E
authors.initials: JE
authors.lastname: Garber
authors.forename: Beth N
authors.initials: BN
authors.lastname: Peshkin
authors.forename: Caryn
authors.initials: C
authors.lastname: Lerman
authors.forename: Patrice
authors.initials: P
authors.lastname: Watson
authors.forename: Henry T
authors.initials: HT
authors.lastname: Lynch
authors.forename: Susan G
authors.initials: SG
authors.lastname: Hilsenbeck
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Rubinstein
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Hughes
authors.forename: Giovanni
authors.initials: G
authors.lastname: Parmigiani
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000517:prevention & control; D018567:Breast Neoplasms, Male / Q000453:epidemiology / Q000235:genetics / Q000517:prevention & control; D003658:Decision Making, Computer-Assisted; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000517:prevention & control; D010375:Pedigree; D015995:Prevalence; D011336:Probability; D015203:Reproducibility of Results; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D014481:United States / Q000453:epidemiology