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Original article
Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks
  1. Brennan Decker1,2,
  2. Jamie Allen1,
  3. Craig Luccarini3,
  4. Karen A Pooley1,
  5. Mitul Shah3,
  6. Manjeet K Bolla1,
  7. Qin Wang1,
  8. Shahana Ahmed3,
  9. Caroline Baynes1,
  10. Don M Conroy1,
  11. Judith Brown1,
  12. Robert Luben1,
  13. Elaine A Ostrander2,
  14. Paul DP Pharoah1,3,
  15. Alison M Dunning3,
  16. Douglas F Easton1,3
  1. 1 Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK
  2. 2 Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
  3. 3 Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK
  1. Correspondence to Professor Douglas F Easton, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; dfe20{at}


Background Breast cancer (BC) is the most common malignancy in women and has a major heritable component. The risks associated with most rare susceptibility variants are not well estimated. To better characterise the contribution of variants in ATM, CHEK2, PALB2 and XRCC2, we sequenced their coding regions in 13 087 BC cases and 5488 controls from East Anglia, UK.

Methods Gene coding regions were enriched via PCR, sequenced, variant called and filtered for quality. ORs for BC risk were estimated separately for carriers of truncating variants and of rare missense variants, which were further subdivided by functional domain and pathogenicity as predicted by four in silico algorithms.

Results Truncating variants in PALB2 (OR=4.69, 95% CI 2.27 to 9.68), ATM (OR=3.26; 95% CI 1.82 to 6.46) and CHEK2 (OR=3.11; 95% CI 2.15 to 4.69), but not XRCC2 (OR=0.94; 95% CI 0.26 to 4.19) were associated with increased BC risk. Truncating variants in ATM and CHEK2 were more strongly associated with risk of oestrogen receptor (ER)-positive than ER-negative disease, while those in PALB2 were associated with similar risks for both subtypes. There was also some evidence that missense variants in ATM, CHEK2 and PALB2 may contribute to BC risk, but larger studies are necessary to quantify the magnitude of this effect.

Conclusions Truncating variants in PALB2 are associated with a higher risk of BC than those in ATM or CHEK2. A substantial risk of BC due to truncating XRCC2 variants can be excluded.

  • Cancer: breast
  • Genetic Epidemiology
  • Evidence Based Practice
  • Geneticscreening/counselling

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  • Contributors BD designed the targeted sequencing panel, performed bioinformatics and statistical analyses, and drafted the manuscript. JA performed bioinformatics analysis. CL and AMD coordinated the targeted sequencing and AMD also assisted with drafting the manuscript. KAP and SA contributed Sanger validation of variant calls. MS, MKB and QW provided data management support. CB, DMC and JB prepared targeted sequencing libraries. RL provided samples and phenotypic data from EPIC. EAO assisted with drafting the manuscript. PDPP coordinated SEARCH. DFE conceived and designed the study, performed statistical analysis and assisted with drafting the manuscript. All authors read and approved the final manuscript.

  • Funding Cancer Research UK (C490/A10124, C1287/A16563, C8197/A16565), NIH, NHGRI

  • Competing interests No, there are no competing interests.

  • Patient consent Obtained.

  • Ethics approval Cambridgeshire Research Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Collaborators Maaike Vreeswijk.

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