The c.156_157insAlu BRCA2 mutation has so far only been reported in hereditary breast/ovarian cancer (HBOC) families of Portuguese origin. Since this mutation is not detectable using the commonly used screening methodologies and must be specifically sought, we screened for this rearrangement in a total of 5,440 suspected HBOC families from 22 labs from 13 countries from several continents. Whereas the c.156_157insAluBRCA2 mutation was detected in 11 of 149 suspected HBOC families from Portugal, representing 37.9% of all deleterious mutations, in other countries it was detected only in one proband living in France and in four individuals requesting predictive testing living in France and in the USA, all having in common the fact that they are relatively recent immigrants of Portuguese origin in those countries. After performing an extensive haplotype study in carrier families, we estimate that this founder mutation has occurred 558±215 years ago. We further demonstrate significant quantitative differences regarding the production of the BRCA2 full length RNA and the transcript with exon 3 skipping in c.156_157insAlu BRCA2 mutation carriers and in controls, indicating that disruption of alternative transcript ratios is the mechanism causing hereditary breast/ovarian cancer associated with this BRCA2 rearrangement. We further show that the cumulative incidence of breast cancer in c.156_157insAlu BRCA2 mutation carriers does not differ from that of other BRCA2 and BRCA1 pathogenic mutations, further strengthening its role as the major contributor to hereditary predisposition to breast cancer in Portugal. We recommend that all suspected HBOC families from Portugal or with Portuguese ancestry are specifically tested for this rearrangement, ideally prior to screening of the entire coding regions of BRCA1 and BRCA2.3

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