Germ-line mutations within the breast cancer susceptibility genes, BRCA1 and BRCA2 are responsible for inherited susceptibility to breast and ovarian cancer. A wide spectrum of pathogenic mutations has been identified within both genes, but alterations within these genes occur far less frequently than originally believed. A large number of breast cancer families that showed linkage to BRCA1 were not found to carry a pathogenic BRCA1 mutation following the use of “classical” PCR based assays. In 1997, a large genomic rearrangement was reported within BRCA1, using Southern blotting. Numerous groups then employed semi-/quantitative methods to determine the presence and/or frequency of such alterations. This search extended the mutation spectrum of this gene, and to date at least 69 unique rearrangements have been reported. The contribution of these alterations to the burden of breast/ovarian cancer differs greatly between populations ranging from 0% to 36% of all BRCA1 mutations in the Finnish and Dutch populations respectively. Mutation screening has previously indicated that small mutations within the two BRCA genes are responsible for 59% of breast/ovarian cancer susceptibility in South Africa. To determine whether large rearrangements contribute to breast cancer susceptibility in South Africa, 74 BRCA1/2 small mutation negative patients from 58 breast / ovarian cancer families were screened for large intragenic BRCA1 rearrangements using Multiplex Ligation-dependent Probe Amplification (MLPA). In this first study of large genomic rearrangements within BRCA1 in South Africa, three genomic aberrations were detected. A deletion of exon 22 (IVS21-36del510) was identified in a Dutch immigrant. This deletion represents one of the Dutch founder mutations. Both exons 23 and 24 were found deleted in a South African family of Greek ancestry. The breakpoints of this deletion were not characterized. Simultaneous deletions of these two exons (where the breakpoints could not be characterized) have been reported in the Italian and Spanish populations. One of the genomic aberrations detected by MLPA in the present study erroneously appeared as a deletion of exon 18. Sequence analysis of this variant identified it as a single base pair substitution (c.5215G_A). This variant (R1699Q) has been reported previously, but its pathological significance is unconfirmed. In total, two large genomic rearrangements were detected in two families, of which only one is a South African, of Greek ancestry. This indicates that such mutations play a small role (1.75%; 1/57) in familial breast / ovarian cancer in South Africa (Dutch immigrant excluded). No rearrangements were identified in the Afrikaner population, indicating that such mutations do not contribute to the burden of familial breast/ovarian cancer in this population (0/40). The remaining South African breast/ovarian cancer risk may to some extent be explained by large rearrangements within BRCA2, or by mutations in other low penetrance breast cancer susceptibility gene(s). BRCA2 will now be screened by MLPA, followed by mutation screening of genes such as p53 and CHEK2 in high-risk families.