title: Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer.
abstract: BACKGROUND
  The incidence of breast cancer has doubled over the past 20 years in the Czech Republic. Hereditary factors may be a cause of young onset, bilateral breast or ovarian cancer, and familial accumulation of the disease. BRCA1 and BRCA2 mutations account for an important fraction of hereditary breast and ovarian cancer cases. One thousand and ten unrelated high-risk probands with breast and/or ovarian cancer were analysed for the presence of a BRCA1 or BRCA2 gene mutation at the Masaryk Memorial Cancer Institute (Czech Republic) during 1999-2006.
  
  
  METHODS
  The complete coding sequences and splice sites of both genes were screened, and the presence of large intragenic rearrangements in BRCA1 was verified. Putative splice-site variants were analysed at the cDNA level for their potential to alter mRNA splicing.
  
  
  RESULTS
  In 294 unrelated families (29.1% of the 1,010 probands) pathogenic mutations were identified, with 44 different BRCA1 mutations and 41 different BRCA2 mutations being detected in 204 and 90 unrelated families, respectively. In total, three BRCA1 founder mutations (c.5266dupC; c.3700_3704del5; p.Cys61Gly) and two BRCA2 founder mutations (c.7913_7917del5; c.8537_8538del2) represent 52% of all detected mutations in Czech high-risk probands. Nine putative splice-site variants were evaluated at the cDNA level. Three splice-site variants in BRCA1 (c.302-3C>G; c.4185G>A and c.4675+1G>A) and six splice-site variants in BRCA2 (c.475G>A; c.476-2>G; c.7007G>A; c.8755-1G>A; c.9117+2T>A and c.9118-2A>G) were demonstrated to result in aberrant transcripts and are considered as deleterious mutations.
  
  
  CONCLUSIONS
  This study represents an evaluation of deleterious genetic variants in the BRCA1 and 2 genes in the Czech population. The classification of several splice-site variants as true pathogenic mutations may prove useful for genetic counselling of families with high risk of breast and ovarian cancer.
authors.affiliation: Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic. emachack@mou.cz
authors.forename: Eva
authors.initials: E
authors.lastname: Machackova
authors.forename: Lenka
authors.initials: L
authors.lastname: Foretova
authors.forename: Mirka
authors.initials: M
authors.lastname: Lukesova
authors.forename: Petra
authors.initials: P
authors.lastname: Vasickova
authors.forename: Marie
authors.initials: M
authors.lastname: Navratilova
authors.forename: Ilse
authors.initials: I
authors.lastname: Coene
authors.forename: Hana
authors.initials: H
authors.lastname: Pavlu
authors.forename: Veronika
authors.initials: V
authors.lastname: Kosinova
authors.forename: Jitka
authors.initials: J
authors.lastname: Kuklova
authors.forename: Kathleen
authors.initials: K
authors.lastname: Claes
mesh_terms: D017668:Age of Onset; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D018567:Breast Neoplasms, Male / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D018153:Czech Republic; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009154:Mutation; D010051:Ovarian Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D012307:Risk Factors
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein