title: Mutation detection rates associated with specific selection criteria for BRCA1/2 testing in 1854 high-risk families: A monocentric Italian study.
abstract: BACKGROUND
  BRCA mutation screening is frequently offered on the basis of the fulfillment of empirical selection criteria, thought to be indicative of a genetic predisposition to breast/ovarian cancer (BrCa/OvCa). This study aimed to evaluate, in a large cohort of BrCa/OvCa families, the mutation detection rate (DR) associated with specific clinical features and the relative performance of the employed selection criteria.
  
  
  METHODS
  BRCA gene analysis was performed on 1854 family probands. The Fisher exact test was used to compare the DRs associated with different clinical features. In a subset of families fulfilling only mutually exclusive criteria, odds ratios and 95% CI were estimated to test the relative effectiveness of each criterion.
  
  
  RESULTS
  The overall DR was 29.3%. Among BrCa-only families, the DRs were significantly higher in the presence of early-onset compared with late-onset cases, and of bilateral compared with unilateral cases. In families with bilateral cases, ages at diagnosis of both the first and second tumour were significantly lower in mutation carriers. In families fulfilling mutually exclusive criteria, OvCa was the best predictor of BRCA mutations, with DRs (range: 31.8%-80.0%) significantly higher compared with the other criteria. Conversely, isolated early-onset BrCa and three or more late-onset BrCa displayed significantly lower predictive values (7.9% and 7.2%, respectively).
  
  
  CONCLUSIONS
  The observed estimates, albeit confirming a DR above 10% for most of the considered criteria, highlighted some relevant differences among them. Such differences should be taken into account in the identification of patients who might benefit from genetic counselling and subsequent testing.
authors.affiliation: Medical Genetics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: Jacopo.Azzollini@istitutotumori.mi.it.
authors.forename: Jacopo
authors.initials: J
authors.lastname: Azzollini
authors.affiliation: Medical Genetics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: giulietta.scuvera@hotmail.it.
authors.forename: Giulietta
authors.initials: G
authors.lastname: Scuvera
authors.affiliation: Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of Biomedical Sciences for Health, University of Milan, Italy. Electronic address: Eleonora.Bruno@istitutotumori.mi.it.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Bruno
authors.affiliation: Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: Patrizia.Pasanisi@istitutotumori.mi.it.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Pasanisi
authors.affiliation: Medical Genetics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: Daniela.Zaffaroni@istitutotumori.mi.it.
authors.forename: Daniela
authors.initials: D
authors.lastname: Zaffaroni
authors.affiliation: Medical Genetics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: mariarosaria.calvello@yahoo.it.
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Calvello
authors.affiliation: Department of Medical Sciences, University of Turin, Italy; Department of Predictive Medicine and Prevention, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: barbara.pasini@unito.it.
authors.forename: Barbara
authors.initials: B
authors.lastname: Pasini
authors.affiliation: Molecular Bases of Genetic Risk and Genetic Testing Unit, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: Carla2.Ripamonti@istitutotumori.mi.it.
authors.forename: Carla B
authors.initials: CB
authors.lastname: Ripamonti
authors.affiliation: Molecular Bases of Genetic Risk and Genetic Testing Unit, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: Mara.Colombo@istitutotumori.mi.it.
authors.forename: Mara
authors.initials: M
authors.lastname: Colombo
authors.affiliation: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy; Cogentech Cancer Genetics Test Laboratory, Milan, Italy. Electronic address: valeria.pensotti@ifom.eu.
authors.forename: Valeria
authors.initials: V
authors.lastname: Pensotti
authors.affiliation: Molecular Bases of Genetic Risk and Genetic Testing Unit, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: paolo.radice@istitutotumori.mi.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Radice
authors.affiliation: Medical Genetics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: Bernard.Peissel@istitutotumori.mi.it.
authors.forename: Bernard
authors.initials: B
authors.lastname: Peissel
authors.affiliation: Medical Genetics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: Siranoush.Manoukian@istitutotumori.mi.it.
authors.forename: Siranoush
authors.initials: S
authors.lastname: Manoukian
mesh_terms: D000328:Adult; D004252:DNA Mutational Analysis; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D005820:Genetic Testing; D061325:Hereditary Breast and Ovarian Cancer Syndrome / Q000175:diagnosis* / Q000235:genetics; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018579:Patient Selection; D018570:Risk Assessment
keywords: BRCA1 gene; BRCA2 gene; Genetic testing; Hereditary breast and ovarian cancer syndrome; Selection criteria