Incorporating truncating variants in PALB2, CHEK2, and ATM into the BOADICEA breast cancer risk model

Genet Med. 2016 Dec;18(12):1190-1198. doi: 10.1038/gim.2016.31. Epub 2016 Apr 14.


Purpose: The proliferation of gene panel testing precipitates the need for a breast cancer (BC) risk model that incorporates the effects of mutations in several genes and family history (FH). We extended the BOADICEA model to incorporate the effects of truncating variants in PALB2, CHEK2, and ATM.

Methods: The BC incidence was modeled via the explicit effects of truncating variants in BRCA1/2, PALB2, CHEK2, and ATM and other unobserved genetic effects using segregation analysis methods.

Results: The predicted average BC risk by age 80 for an ATM mutation carrier is 28%, 30% for CHEK2, 50% for PALB2, and 74% for BRCA1 and BRCA2. However, the BC risks are predicted to increase with FH burden. In families with mutations, predicted risks for mutation-negative members depend on both FH and the specific mutation. The reduction in BC risk after negative predictive testing is greatest when a BRCA1 mutation is identified in the family, but for women whose relatives carry a CHEK2 or ATM mutation, the risks decrease slightly.

Conclusions: The model may be a valuable tool for counseling women who have undergone gene panel testing for providing consistent risks and harmonizing their clinical management. A Web application can be used to obtain BC risks in clinical practice ( Med 18 12, 1190-1198.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age Factors
  • Aged
  • Aged, 80 and over
  • Ataxia Telangiectasia Mutated Proteins / genetics*
  • BRCA1 Protein / genetics
  • BRCA2 Protein / genetics
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Checkpoint Kinase 2 / genetics*
  • Fanconi Anemia Complementation Group N Protein
  • Female
  • Genetic Predisposition to Disease
  • Genetic Testing
  • Humans
  • Middle Aged
  • Mutation
  • Nuclear Proteins / genetics*
  • Risk Assessment
  • Tumor Suppressor Proteins / genetics*


  • BRCA1 Protein
  • BRCA2 Protein
  • BRCA2 protein, human
  • Fanconi Anemia Complementation Group N Protein
  • Nuclear Proteins
  • PALB2 protein, human
  • Tumor Suppressor Proteins
  • Checkpoint Kinase 2
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK2 protein, human