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

Numerous genetic factorsthat influence breast cancer risk are known. However, approximately two-thirds of the overall familialrisk remain unexplained. To determine whether some of the missing heritability is due to rare variants conferring high tomoderate risk, we tested for an association between the c.5791C>T nonsense mutation (p.Arg1931*; rs144567652) in exon 22 ofFANCMgene and breast cancer. An analysis of genotyping data from 8635 familial breast cancer cases and 6625 controls fromdifferent 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 withcarriers 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-basedprediction, we established that the mutation caused an out-of-frame deletion of exon 22, due to the creation of a binding site forthe pre-mRNA processing protein hnRNP A1. Furthermore, genetic complementation analyses showed that the mutationinfluenced the DNA repair activity of the FANCM protein. In summary, we provide evidence for thefirst time showing that thecommon p.Arg1931* loss-of-function variant inFANCMis a risk factor for familial breast cancer.