PALB2 interacts with BRCA2, and biallelic mutations in PALB2 (also known as FANCN), similar to biallelic BRCA2 mutations, cause Fanconi anemia. We identified monoallelic truncating PALB2 mutations in 10/923 individuals with familial breast cancer compared with 0/1,084 controls (P = 0.0004) and show that such mutations confer a 2.3-fold higher risk of breast cancer (95% confidence interval (c.i.) = 1.4–3.9, P = 0.0025). The results show that PALB2 is a breast cancer susceptibility gene and further demonstrate the close relationship of the Fanconi anemia–DNA repair pathway and breast cancer predisposition.

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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 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.K. is supported by a grant from the Breast Cancer Campaign. A.E. is supported by US Army Medical Research and Material Command grant W81XWH-05-1-0204. This research was supported by donations from the Geoffrey Berger and Daniel Falkner Charitable Trusts, by the Institute of Cancer Research and by Cancer Research UK.

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  1. Section of Cancer Genetics, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.

    • Nazneen Rahman
    • , Sheila Seal
    • , Patrick Kelly
    • , Anthony Renwick
    • , Anna Elliott
    • , Sarah Reid
    • , Katarina Spanova
    • , Rita Barfoot
    • , Tasnim Chagtai
    • , Hiran Jayatilake
    • , Sandra Hanks
    •  & Michael R Stratton
  2. Cancer Research UK Genetic Epidemiology Unit, Strangeways Research Laboratories, University of Cambridge, UK.

    • Deborah Thompson
    • , Lesley McGuffog
    •  & Douglas F Easton
  3. Department of Medical Genetics, St. Mary's Hospital, Manchester M13 0JH, UK.

    • D Gareth Evans
  4. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton SO16 6YA, UK.

    • Diana Eccles
  5. Cancer Genome Project, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambs CB10 1SA, UK.

    • Michael R Stratton


  1. The Breast Cancer Susceptibility Collaboration (UK)


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The study was designed by N.R. and M.R.S. The molecular analyses were performed by S.S., P.K., A.R., S.R., K.S., R.B., T.C., H.J. and S.H. under the direction of N.R. The statistical analyses were performed by D.T., A.E. and L.M. under the direction of D.F.E. The familial collections were initiated by D.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.

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Nazneen Rahman.

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  1. 1.

    Supplementary Table 1

    FANCN (also known as PALB2) nontruncating coding variants.

  2. 2.

    Supplementary Methods

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