1. International distribution and age estimation of the Portuguese BRCA2 c.156_157insAlu founder mutation
- Author
-
Ana Peixoto, Catarina Santos, Manuela Pinheiro, Pedro Pinto, Marie-Jose Soares, Patricia Rocha, Leonor Gusmao, Antonio Amorim, Annemarie Van Der Hout, Anne-Marie Gerdes, Mads Thomassen, Torben Kruse, Dorthe Cruger, Lone Sunde, Yves-Jean Bignon, Nancy Uhrhammer, Lucy Cornil, Etienne Rouleau, Rosette Lidereau, Drakoulis Yannoukakos, Maroulio Pertesi, Steven Narod, Robert Royer, Maurizio Costa, Conxi Lazaro, Lidia Feliubadalo, Begona Grana, Ignacio Blanco, La Hoya, M., Trinidad Caldes, Philippe Maillet, Gaelle Benais-Pont, Bruno Pardo, Yael Laitman, Eitan Friedman, Velasco, Eladio A., Mercedes Duran, Maria-Dolores Miramar, Ana Rodgriguez Valle, Maria-Teresa Calvo, Ana Vega, Ana Blanco, Orland Diez, Sara Gutierrez-Enriquez, Judith Balmana, Ramon Cajal, Teresa Y., Montserrat Baiget, William Foulkes, Marc Tischkowitz, Rachel Kyle, Nelly Sabbaghian, Patricia Ashton-Prolla, Ingrid Ewald, Thangarajan Rajkumar, Luisa Mota-Vieira, Giuseppe Giannini, Alberto Gulino, Achatz, Maria I., Carraro, Dirce M., Brigitte Bresac De Paillerets, Audrey Remenieras, Cindy Benson, Silvia Casadei, Mary-Claire King, Erik Teugels, Teixeira, Manuel R., and Laboratory of Molecular and Medical Oncology
- Subjects
Age estimation ,c.156_157insAlu BRCA2 mutation ,founder mutation ,skin and connective tissue diseases - Abstract
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 5,443 suspected HBOC families from several countries. Whereas the c.156_157insAlu BRCA2 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 being Portuguese immigrants. After performing an extensive haplotype study in carrier families, we estimate that this founder mutation occurred 558 ± 215 years ago. We further demonstrate significant quantitative differences regarding the production of the BRCA2 full length RNA and the transcript lacking exon 3 in c.156_157insAlu BRCA2 mutation carriers and in controls. The cumulative incidence of breast cancer in carriers did not differ from that of other BRCA2 and BRCA1 pathogenic mutations. We recommend that all suspected HBOC families from Portugal or with Portuguese ancestry are specifically tested for this rearrangement.