Large genomic rearrangements of the BRCA1 and BRCA2 genes: review of the literature and report of a novel BRCA1 mutation

Abstract

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.

Frequency of Rearrangements Versus Small Indels Mutations in BRCA1 and BRCA2 Genes in Turkish Patients with High Risk Breast and Ovarian Cancer

“…Our results confirmed the higher prevalence of rearrangements in the BRCA1 gene versus the BRCA2 gene documented in previous reports (21)(22)(23)(24)(25).…”

Next-generation sequencing meets genetic diagnostics: development of a comprehensive workflow for the analysis of BRCA1 and BRCA2 genes

“…[7][8][9] Moreover, large genomic rearrangements (LGRs) of these genes require the use of other complementary techniques. 10,11 The development of cost-effective BRCA mutation detection workflows will not only benefit the genetic counseling process for patients with HBOCS but will also enhance the process of selecting patients for personalized treatments, as could be the case of PARP inhibitors, for example. Mutation analyses of BRCA1 and BRCA2 using NGS have been already performed for high-capacity NGS platforms, such as the 454 FLX (Roche), 12 the Helicos (Heliscope), 13 the Genome Analyzer (Illumina) 4 and, very recently, the GS Junior instrument.…”

Current status and future potential of somatic mutation testing from circulating free DNA in patients with solid tumours

“…In familial cancer syndromes, germline mutations predispose to malignant transformation and often result in earlier onset disease (Gatalica and Torlakovic 2008;Sluiter and van Rensburg 2011). In contrast, in more common sporadic cancers, the tumour usually originates from clonal expansion of a transformed cell through the accumulation of serial somatic mutations ).…”