Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles


We identified constitutional truncating mutations of the BRCA1-interacting helicase BRIP1 in 9/1,212 individuals with breast cancer from BRCA1/BRCA2 mutation–negative families but in only 2/2,081 controls (P = 0.0030), and we estimate that BRIP1 mutations confer a relative risk of breast cancer of 2.0 (95% confidence interval = 1.2–3.2, P = 0.012). Biallelic BRIP1 mutations were recently shown to cause Fanconi anemia complementation group J. Thus, inactivating truncating mutations of BRIP1, similar to those in BRCA2, cause Fanconi anemia in biallelic carriers and confer susceptibility to breast cancer in monoallelic carriers.

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Figure 1: Abridged pedigrees of nine breast cancer families with BRIP1 mutations.


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We thank the participating families who were recruited to the study by the Familial Breast Cancer Collaboration (UK), which includes the following contributors: A. Ardern-Jones, J. Berg, A. Brady, N. Bradshaw, C. Brewer, G. Brice, B. Bullman, J. Campbell, B. Castle, R. Cetnarsryj, C. Chapman, C. Chu, N. Coates, T. Cole, R. Davidson, A. Donaldson, H. Dorkins, F. Douglas, D. Eccles, R. Eeles, F. Elmslie, D.G. Evans, S. Goff, S. Goodman, D. Goudie, J. Gray, L. Greenhalgh, H. Gregory, N. Haites, S.V. Hodgson, T. Homfray, R.S. Houlston, L. Izatt, L. Jeffers, V. Johnson-Roffey, F. Kavalier, C. Kirk, F. Lalloo, I. Locke, M. Longmuir, J. Mackay, A. Magee, S. Mansour, Z. Miedzybrodzka, J. Miller, P. Morrison, V. Murday, J. Paterson, M. Porteous, N. Rahman, M. Rogers, S. Rowe, S. Shanley, A. Saggar, G. Scott, L. Side, L. Snadden, M. Steel, M. Thomas and S. Thomas. We thank A. Hall and E. Mackie for coordination of sample collection. We are grateful for the support of the Daniel Faulkner Trust and the Geoffrey Berger Charitable Trust. We acknowledge use of DNA from the British 1958 Birth Cohort collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. P. Kelly is supported by a grant from the Breast Cancer Campaign. M.A., B.N. and A.E. are supported by US Army Medical Research and Material Command grant #W81XWH-05-1-0204. This research was supported by the Institute of Cancer Research and Cancer Research UK.

Author information

The study was designed by N.R. and M.R.S. The molecular analyses were performed by S.S., A.R., P.K., R.B., T.C., H.J., M.A. and K.S. under the direction of N.R. The statistical analyses were performed by D.T., A.E., B.N. and L.M. under the direction of D.F.E. The familial collections were initiated by G.E. and D.E. and were collected by the Breast Cancer Susceptibility Collaboration (UK). The manuscript was written by N.R. and M.R.S.

Correspondence to Nazneen Rahman.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Primers and PCR conditions for BRIP1 coding exons. (PDF 9 kb)

Supplementary Table 2

Nonsynonymous BRIP1 missense variants in breast cancer cases and controls. (PDF 8 kb)

Supplementary Methods (PDF 21 kb)

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