title: BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families.
abstract: Worldwide variation in the distribution of BRCA1 and BRCA2 mutations is well recognised, and for the Belgian population no comprehensive studies about BRCA1/2 mutation spectra or frequencies have been published. We screened the complete coding region of both genes in 451 individuals from 349 Belgian families referred to a family cancer clinic and identified 49 families with a BRCA1 and 26 families with a BRCA2 mutation. Six major recurrent mutations (BRCA1 IVS5+3A>G, 2478-2479insG, E1221X and BRCA2 IVS6+1G>A, 6503-6504delTT, 9132delC) accounted for nearly 60% of all mutations identified. Besides 75 true pathogenic mutations, we identified several variants of unknown clinical significance. In combination with a family history, an early average age of female breast cancer diagnosis (P<0.001), and the presence of a relative with ovarian cancer (P<0.0001) or multiple primary breast cancers (P=0.002), increased the chance for finding a mutation. Male breast cancer was indicative of a BRCA2 mutation segregating in the family (P=0.002). Mutations in the 5'-end of BRCA1 and BRCA2 were associated with a significantly increased risk for ovarian cancer relative to the central portion of the gene. Our study suggests a role for additional breast cancer susceptibility genes in the Belgian population, since mutation detection ratios were low in high-risk breast cancer-only families as compared to breast-ovarian cancer families. Given the large proportion of recurring mutations, molecular testing can now be organised in a more cost-effective way. Our data allow optimisation of genetic counselling and disease prevention in Belgian breast/ovarian cancer families.
authors.affiliation: Centre for Medical Genetics, Ghent University Hospital, De Pintelaan 185, Gent 9000, Belgium. kathleen.claes@ugent.be
authors.forename: K
authors.initials: K
authors.lastname: Claes
authors.forename: B
authors.initials: B
authors.lastname: Poppe
authors.forename: I
authors.initials: I
authors.lastname: Coene
authors.forename: A De
authors.initials: AD
authors.lastname: Paepe
authors.forename: L
authors.initials: L
authors.lastname: Messiaen
mesh_terms: D000328:Adult; D000368:Aged; D001530:Belgium; D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D005820:Genetic Testing; D005828:Genetics, Population; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics*; D010375:Pedigree; D012307:Risk Factors