Growing recognition of the role for rare missense substitutions in breast cancer susceptibility

Biomark Med. 2014;8(4):589-603. doi: 10.2217/bmm.13.143.


Most cancer susceptibility genes function as tumor suppressors; accordingly, the focus of mutation screening in breast cancer families has been to identify protein-truncating mutations. However, it is now clear that, for some breast cancer susceptibility genes, a significant proportion of the burden of disease comes from rare missense substitutions. Among genes that have been extensively evaluated, BRCA1, BRCA2, PALB2 and BRIP1 stand as examples where the majority of mutations lead to protein truncation;TP53 provides a counter example, where the majority of pathogenic variants are missense substitutions. In ATM and CHEK2, missense substitutions are probably equally or more important in terms of their frequency and attributable risk. Therefore, ongoing efforts to identify new susceptibility genes should not ignore missense variation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / genetics
  • BRCA1 Protein / genetics
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Checkpoint Kinase 2 / genetics
  • DNA-Binding Proteins / genetics
  • Disease Susceptibility
  • Fanconi Anemia Complementation Group N Protein
  • Fanconi Anemia Complementation Group Proteins
  • Female
  • Humans
  • Mutation, Missense
  • Nuclear Proteins / genetics
  • RNA Helicases / genetics
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Proteins / genetics


  • BRCA1 Protein
  • DNA-Binding Proteins
  • Fanconi Anemia Complementation Group N Protein
  • Fanconi Anemia Complementation Group Proteins
  • Nuclear Proteins
  • PALB2 protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Checkpoint Kinase 2
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK2 protein, human
  • BRIP1 protein, human
  • RNA Helicases