Global sequence diversity of BRCA2: analysis of 71 breast cancer families and 95 control individuals of worldwide populations [published erratum appears in Hum Mol Genet 1999 Apr;8(4):717-9]

The aim of this study was to evaluate the prevalence of simple sequencevariation in the BRCA2 gene. To this end, 71 breast and breast-ovariancancer (HBC/HBOC) families along with 95 control individuals from a widerange of ethnicities were analyzed by means of denaturing high- performanceliquid chromatography (DHPLC) and direct sequence analysis. In the coding(10 257 bp) and non-coding (2799 bp) sequences of BRCA2, 82 sequencevariants were identified. Three different, apparently disease-associatedBRCA2 mutations were found in six HBC/HBOC families (8%): two splice sitemutations in introns 5 and 21, and one frameshift mutation in exon 11. Inthe coding region, 53 simple sequence variants were found: 35 missensemutations, one 2 bp deletion (CT) resulting in a stop at codon 3364, onenonsense mutation with a stop at codon 3326, one deletion of a completecodon (AAA) resulting in the loss of leucine, and 15 silent mutations. Inthe non-coding region, 26 polymorphisms were detected. Of the 79 sequencevariants that were not obviously disease-associated, eight were detectedonly in HBC/HBOC families. The remaining 71 variants were identified inboth HBC/HBOC families and control individuals. Sixty three sequencevariants (80%) were specific for a continent. Forty two percent (33 out of79) of the sequence variants were detected exclusively in Africa, thoughonly 13% of the 332 chromosomes screened were of African origin. Our dataindicate that, in BRCA2, simple sequence variation is frequent [in thecoding region 1 in 194 bp (straight theta = 2.2 x 10(-4)), and in thenon-coding region 1 in 108 bp (straight theta = 4.4 x 10(-4)),respectively].