Germline mutations in BRCA1 and BRCA2 increase the risk for developing breast and ovarian cancer. Previously, the techniques available allowed only for the identification of small genomic alterations, but the dawn of new technology now allows for the rapid detection of large genomic rearrangements (LGRs). LGRs in BRCA1 are responsible for between 0 and 27% of all BRCA1 disease-causing mutations identified in numerous populations. Such alterations are far less common in the BRCA2 gene. To determine the impact of BRCA1 and BRCA2 LGRs in South Africa, 52 hereditary breast and/or ovarian South African families (36 were Afrikaners) were screened for BRCA1 and BRCA2 LGRs using multiplex ligation-dependent probe amplification. These patients were previously shown to be BRCA1 and BRCA2 small mutation negative. One LGR was detected in BRCA1 in a South African family with Greek ancestry. This is a novel deletion of both exons 23 and 24 (NG_005905.2:g.169527_180579del). This first study of BRCA rearrangements in South Africa reveals that LGRs comprise ~3% of identified BRCA1 mutations, a low rate in comparison to other populations. In addition, we have reviewed all 98 previously characterized BRCA1/2 LGRs and re-named them according to the recommended HGVS nomenclature, using the recently released RefSeqGene records, NG_005905.2 and NG_012772.1 for BRCA1 and BRCA2. A standardized resource is now provided which will assist researchers in determining whether their LGRs are novel. Furthermore, we have clarified some of the previously misunderstood rules of nomenclature, which will make uniform reporting of BRCA1/2 easier in the future.

Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

PALB2 (partner and localizer of BRCA2) is a recently identified breast cancer susceptibility gene, in which mutations confer doubling of breast cancer risk with moderate to low penetrance. Recent studies in various populations report that deleterious mutations in this gene account for approximately 1% of familial or early-onset breast cancer cases. This study aimed to determine the involvement of PALB2 mutations in a cohort of 48 young (29-45 years) South African breast cancer patients unselected for family history of breast cancer. The complete coding region and intron-exon boundaries of PALB2 were analyzed. A novel truncating mutation, c.697delG (V233fs) was identified in one patient. A missense variant (E211G), identified in another patient, appears to be segregating with the disease, but in silico analysis using SIFT, PolyPhen and A-GVGD, indicates that this variant is nonpathogenic. In addition, four other missense, one synonymous and three intronic variants were detected, all of which appear polymorphic. This represents the second study to analyze the role of PALB2 in early-onset breast cancer patients unselected for family history. The first study, of a Chinese population, established that PALB2 was responsible for 1.3% of early-onset breast cancer cases. Our study reports that deleterious mutations in PALB2 account for approximately 2% (1/48) of South African early-onset breast cancer.

Breast cancer is the most common malignancy among women in South Africa, with a crude incidence rate of 18.5/100 000 recorded between 1993 and 1995.1 A small but significant percentage (5 -10%) of breast cancer cases are directly due to an inherited susceptibility.2 Two tumour suppressor genes involved in early-onset breast and ovarian cancer, BRCA1 and BRCA2, have been mapped and cloned. 3,4 These two genes explain 20 -40% of heritable breast cancer cases in various populations over the world. 5,6 A large linkage and mutation study on 237 families collected by the Breast Cancer Linkage Consortium found that overall BRCA1 accounts for 52% of all families, and BRCA2 for 32%, leaving 16% of the families with a familial breast cancer phenotype unaccounted for. 7 In the study, 81% of the families with both a breast and an ovarian phenotype were BRCA1-positive families while 14% linked to BRCA2. The situation was reversed in families that presented with a male breast cancer phenotype in addition to female breast cancer, where 76% linked to BRCA2 and only a small percentage to BRCA1.Worldwide many families with a strong history of familial breast cancer have been fully screened for BRCA1 and BRCA2 mutations but none were found. This is especially the case in breast cancer-specific families (no other cancers beside breast cancer in family). While the search for the BRCA1 and BRCA2 genes was helped by the strong association of ovarian cancer in addition to breast cancer with BRCA1 and male breast cancer with BRCA2, the search for other breast cancer-associated genes is more complicated. Studies on BRCA1-and 2-negative breast cancer families showed that the most probable explanation is that there are multiple additional genes with lower penetrance and/or prevalence, each responsible for a small number of families. 8,9