FANCM c.5791C>T nonsense mutation (rs144567652) induces exon skipping, affects DNA repair activity and is a familial breast cancer risk factor

Paolo Peterlongo, Irene Catucci, Mara Colombo, Laura Caleca, Eliseos Mucaki, Massimo Bogliolo, Maria Marin, Francesca Damiola, Loris Bernard, Valeria Pensotti, Sara Volorio, Valentina Dall'Olio, Alfons Meindl, Claus Bartram, Christian Sutter, Harald Surowy, Valérie Sornin, Marie Gabrielle Dondon, Séverine Eon-Marchais, Dominique Stoppa-LyonnetNadine Andrieu, Olga M. Sinilnikova, Gillian Mitchell, Paul A. James, Ella Thompson, Marina Marchetti, Cristina Verzeroli, Carmen Tartari, Gabriele Lorenzo Capone, Anna Laura Putignano, Maurizio Genuardi, Veronica Medici, Isabella Marchi, Massimo Federico, Silvia Tognazzo, Laura Matricardi, Simona Agata, Riccardo Dolcetti, Lara Della Puppa, Giulia Cini, Viviana Gismondi, Valeria Viassolo, Chiara Perfumo, Maria Antonietta Mencarelli, Margherita Baldassarri, Bernard Peissel, Gaia Roversi, Valentina Silvestri, Piera Rizzolo, Francesca Spina, Caterina Vivanet, Maria Grazia Tibiletti, Maria Adelaide Caligo, Gaetana Gambino, Stefania Tommasi, Brunella Pilato, Carlo Tondini, Chiara Corna, Bernardo Bonanni, Monica Barile, Ana Osorio, Javier Benitez, Luisa Balestrino, Laura Ottini, Siranoush Manoukian, Marco A. Pierotti, Alessandra Renieri, Liliana Varesco, Fergus J. Couch, Xianshu Wang, Peter Devilee, Florentine S. Hilbers, Christi J. van Asperen, Alessandra Viel, Marco Montagna, Laura Cortesi, Orland Diez, Judith Balmaña, Jan Hauke, Rita K. Schmutzler, Laura Papi, Miguel Angel Pujana, Conxi Lázaro, Anna Falanga, Kenneth Offit, Joseph Vijai, Ian Campbell, Barbara Burwinkel, Anders Kvist, Hans Ehrencrona, Sylvie Mazoyer, Sara Pizzamiglio, Paolo Verderio, Jordi Surralles, Peter K. Rogan, Paolo Radice

Research output: Contribution to journalArticlepeer-review


Numerous genetic factors that influence breast cancer risk are known. However, approximately two-thirds of the overall familial risk remain unexplained. To determine whether some of the missing heritability is due to rare variants conferring high to moderate risk, we tested for an association between the c.5791C>T nonsense mutation (p. Arg1931*; rs144567652) in exon 22 of FANCM gene and breast cancer. An analysis of genotyping data from 8635 familial breast cancer cases and 6625 controls from different countries yielded an association between the c.5791C>T mutation and breast cancer risk [odds ratio (OR) = 3.93 (95% confidence interval (CI) = 1.28-12.11; P = 0.017)]. Moreover, we performed two meta-analyses of studies from countries with carriers in both cases and controls and of all available data. These analyses showed breast cancer associations with OR = 3.67 (95% CI = 1.04-12.87; P = 0.043) and OR = 3.33 (95% CI = 1.09-13.62; P = 0.032), respectively. Based on information theory-based prediction, we established that the mutation caused an out-of-frame deletion of exon 22, due to the creation of a binding site for the pre-mRNA processing protein hnRNP A1. Furthermore, genetic complementation analyses showed that the mutation influenced the DNA repair activity of the FANCM protein. In summary, we provide evidence for the first time showing that the common p. Arg1931* loss-of-function variant in FANCM is a risk factor for familial breast cancer.

Original languageEnglish
Article numberddv251
Pages (from-to)5345-5355
Number of pages11
JournalHuman Molecular Genetics
Issue number18
Publication statusPublished - Apr 9 2015

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology


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