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


ABSTRACT: 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.

SUBMITTER: Peterlongo P 

PROVIDER: S-EPMC4550823 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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

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

Human molecular genetics 20150630 18


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 dif  ...[more]

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