title: Global sequence diversity of BRCA2: analysis of 71 breast cancer families and 95 control individuals of worldwide populations.
abstract: The aim of this study was to evaluate the prevalence of simple sequence variation in the BRCA2 gene. To this end, 71 breast and breast-ovarian cancer (HBC/HBOC) families along with 95 control individuals from a wide range of ethnicities were analyzed by means of denaturing high-performance liquid chromatography (DHPLC) and direct sequence analysis. In the coding (10 257 bp) and non-coding (2799 bp) sequences of BRCA2, 82 sequence variants were identified. Three different, apparently disease-associated BRCA2 mutations were found in six HBC/HBOC families (8%): two splice site mutations in introns 5 and 21, and one frameshift mutation in exon 11. In the coding region, 53 simple sequence variants were found: 35 missense mutations, one 2 bp deletion (CT) resulting in a stop at codon 3364, one nonsense mutation with a stop at codon 3326, one deletion of a complete codon (AAA) resulting in the loss of leucine, and 15 silent mutations. In the non-coding region, 26 polymorphisms were detected. Of the 79 sequence variants that were not obviously disease-associated, eight were detected only in HBC/HBOC families. The remaining 71 variants were identified in both HBC/HBOC families and control individuals. Sixty three sequence variants (80%) were specific for a continent. Forty two percent (33 out of 79) of the sequence variants were detected exclusively in Africa, though only 13% of the 332 chromosomes screened were of African origin. Our data indicate that, in BRCA2, simple sequence variation is frequent [in the coding region 1 in 194 bp (straight theta = 2.2 x 10(-4)), and in the non-coding region 1 in 108 bp (straight theta = 4.4 x 10(-4)), respectively].
authors.affiliation: Division of Senology, Ludwig Boltzmann Institute for Clinical Experimental Oncology, University of Vienna, 1090 Vienna, Austria.
authors.forename: T M
authors.initials: TM
authors.lastname: Wagner
authors.forename: K
authors.initials: K
authors.lastname: Hirtenlehner
authors.forename: P
authors.initials: P
authors.lastname: Shen
authors.forename: R
authors.initials: R
authors.lastname: Moeslinger
authors.forename: D
authors.initials: D
authors.lastname: Muhr
authors.forename: E
authors.initials: E
authors.lastname: Fleischmann
authors.forename: H
authors.initials: H
authors.lastname: Concin
authors.forename: W
authors.initials: W
authors.lastname: Doeller
authors.forename: A
authors.initials: A
authors.lastname: Haid
authors.forename: A H
authors.initials: AH
authors.lastname: Lang
authors.forename: P
authors.initials: P
authors.lastname: Mayer
authors.forename: E
authors.initials: E
authors.lastname: Petru
authors.forename: E
authors.initials: E
authors.lastname: Ropp
authors.forename: G
authors.initials: G
authors.lastname: Langbauer
authors.forename: E
authors.initials: E
authors.lastname: Kubista
authors.forename: O
authors.initials: O
authors.lastname: Scheiner
authors.forename: P
authors.initials: P
authors.lastname: Underhill
authors.forename: J
authors.initials: J
authors.lastname: Mountain
authors.forename: M
authors.initials: M
authors.lastname: Stierer
authors.forename: C
authors.initials: C
authors.lastname: Zielinski
authors.forename: P
authors.initials: P
authors.lastname: Oefner
mesh_terms: D000349:Africa; D024682:BRCA2 Protein; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D016147:Genes, Tumor Suppressor; D014644:Genetic Variation; D006801:Humans; D008297:Male; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics; D010375:Pedigree; D014157:Transcription Factors / Q000235:genetics*