Global sequence diversity of BRCA2: analysis of 71 breast cancer families and 95 control individuals of worldwide populations

The aim of this study was to evaluate the prevalence of simple sequence var iation 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 ch romatography (DHPLC) and direct sequence analysis. In the coding (10 257 bp ) and non-coding (2799 bp) sequences of BRCA2, 82 sequence variants were id entified. Three different, apparently disease-associated BRCA2 mutations we re found in six HBC/HBOC families (8%): two splice site mutations in intron s 5 and 21, and one frameshift mutation in exon 11, In the coding region, 5 3 simple sequence variants were found: 35 missense mutations, one 2 bp dele tion (CT) resulting in a stop at codon 3364, one nonsense mutation with a s top 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 poly morphisms were detected. Of the 79 sequence variants that were not obviousl y disease-associated, eight were detected only in HBC/HBOC families. The re maining 71 variants were identified in both HBC/HBOC families and control i ndividuals. Sixty three sequence variants (80%) were specific for a contine nt, Forty two percent (33 out of 79) of the sequence variants were detected exclusively in Africa, though only 13% of the 332 chromosomes screened wer e of African origin. Our data indicate that, in BRCA2, simple sequence vari ation is frequent [in the coding region 1 in 194 bp (theta = 2.2 x 10(-4)), and in the non-coding region 1 in 108 bp (theta = 4.4 x 10(-4)), respective ly],