Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks

J Med Genet. 2017 Nov;54(11):732-741. doi: 10.1136/jmedgenet-2017-104588. Epub 2017 Aug 4.


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.

Keywords: Cancer: breast; Evidence Based Practice; Genetic Epidemiology; Geneticscreening/counselling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / chemistry
  • Ataxia Telangiectasia Mutated Proteins / genetics*
  • Breast Neoplasms / genetics*
  • Checkpoint Kinase 2 / chemistry
  • Checkpoint Kinase 2 / genetics*
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics*
  • Fanconi Anemia Complementation Group N Protein / chemistry
  • Fanconi Anemia Complementation Group N Protein / genetics*
  • Female
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Humans
  • Sequence Analysis, Protein


  • DNA-Binding Proteins
  • Fanconi Anemia Complementation Group N Protein
  • PALB2 protein, human
  • XRCC2 protein, human
  • Checkpoint Kinase 2
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK2 protein, human