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]

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].

Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population

“…For both groups, higher mutation rates were detected in the BRCA1 gene. Lower frequencies were published for the BRCA2 gene in the Austrian, 43 Belgian 44 and Swedish 45 breast/ovarian cancer populations, although these numbers may be biased by the smaller number of patients investigated in these studies.…”

Association between BRCA1 and BRCA2 mutations and cancer phenotype in Spanish breast/ovarian cancer families: Implications for genetic testing

“…12,14,[23][24][25][26][27] The breast cancer linkage consortium (BCLC) estimates that 95% of breast/ovarian cancer families and 65% of female breast cancer families are related to BRCA1 or BRCA2. 4 We detected mutations in, respectively, 60% (8/13) and 23% (7/30) of our breast/ovarian and female breast cancer families with BCLC entry criteria (at least 4 breast cancer cases).…”

Breast cancer genetics in African Americans

“…45 One disease-related BRCA2 mutation was identified in 88 African-American women with breast cancer. In a worldwide study of 71 breast cancer families and 95 controls, Wagner et al 44 did not identify any deleterious BRCA2 mutations in African-American or African families. Consistent with the greater genetic diversity observed in people of African ancestry, a higher frequency of sequence variations was found in Africans than in other worldwide populations.…”

“…P*: polymorphism in 21 African controls. 26,44 3 of 54 families (6%) with breast cancer only, in 4 of 12 families (33%) with ovarian and breast cancers, in 3 of 35 families (9%) with at least one breast cancer diagnosed before the age 50 and no ovarian cancer, and in 2 of 10 families (20%) with at least one breast cancer diagnosed before the age 50 and ovarian cancer diagnosed at any age. In primarily white women with breast cancer diagnosed before age 50 or ovarian cancer diagnoses at any age and one first-or seconddegree relative with either diagnosis, Frank et al 42 observed BRCA2 mutations at a similar frequency of 11% (13 of 121) in families with breast cancer only and 15% (18 of 117) in families with breast and ovarian cancers.…”