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In the Iberian Peninsula, which includes mainly Spain and Portugal, large genomic rearrangements (LGRs) of  BRCA1  and  BRCA2  have respectively been found in up to 2.33% and 8.4% of families with hereditary breast and/or ovarian cancer (HBOC) that lack point mutations and small indels. In Galicia (Northwest Spain), the spectrum and frequency of  BRCA1/BRCA2  point mutations differs from the rest of the Iberian populations. However, to date there are no Galician frequency reports of  BRCA1/BRCA2  LGRs. Here we used multiplex ligation-dependent probe amplification (MLPA) to screen 651 Galician index cases (out of the 830 individuals referred for genetic analysis) without point mutations or small indels. We identified three different  BRCA1  LGRs in four families. Two of them have been previously classified as pathogenic LGRs: the complete deletion of  BRCA1  (identified in two unrelated families) and the deletion of exons 1 to 13. We also identified the duplication of exons 1 and 2 that is a LGR with unknown pathogenicity. Determination of the breakpoints of the  BRCA1  LGRs using CNV/SNP arrays and sequencing identified them as NG_005905.2:g.70536_180359del, NG_005905.2:g.90012_97270dup, and NC_000017.10:g.41230935_41399840delinsAluSx1, respectively; previous observations of  BRCA1  exon1-24del, exon1-2dup, and exon1-13del LGRs have not characterized them in such detail. All the  BRCA1  LGRs arose from unequal homologous recombination events involving Alu elements. We also detected, by sequencing, one  BRCA2  LGR, the Portuguese founder mutation c.156_157insAluYa5. The low frequency of  BRCA1  LGRs within  BRCA1  mutation carriers in Galicia (2.34%, 95% CI: 0.61–7.22) seems to differ from the Spanish population (9.93%, 95% CI: 6.76–14.27,  P -value = 0.013) and from the rest of the Iberian population (9.76%, 95% CI: 6.69–13.94,  P -value = 0.014).

plos one

Large Genomic Rearrangements of BRCA1 and BRCA2 among Patients Referred for Genetic Analysis in Galicia (NW Spain): Delimitation and Mechanism of Three Novel BRCA1 Rearrangements