Contributions of ATM mutations to familial breast and ovarian cancer

Cancer Res. 2003 Jun 15;63(12):3325-33.


This study addresses the prevalence of ATM mutations and the association with breast cancer in Austrian families selected for a history of breast or ovarian cancer or both [hereditary breast and ovarian cancer (HBOC)]. In 270 HBOC families previously screened for BRCA1 and BRCA2 mutations, 137 different sequence alterations of ATM were identified. Seven of these were mutations presumed to cause ataxia telangiectasia based on their effect on the ATM protein, including five that caused a protein truncation and two missense mutations in the catalytic kinase domain of the highly conserved COOH terminus of the protein. The seven mutations were found in 10 families (3.7%). In addition, one missense variant, L1420F, was observed in 13 HBOC families (4.8%) but was not observed in any of the 122 healthy volunteers with no history of breast cancer. In addition, the variant segregated with breast cancer in some of the families, suggesting that it may be pathogenic for breast cancer. Sixty-two additional variants of potential significance were observed in 65 HBOC families, but not in healthy controls. These variants included 24 sequence alterations with possible effects on splicing or protein-protein interactions. This study indicates that there is a significant prevalence of ATM mutations in breast and ovarian cancer families and adds to a growing body of evidence that ATM mutations confer increased susceptibility to breast cancer.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Amino Acid Substitution
  • Ataxia Telangiectasia Mutated Proteins
  • Austria / epidemiology
  • BRCA2 Protein / genetics
  • Breast Neoplasms / epidemiology
  • Breast Neoplasms / genetics*
  • Breast Neoplasms, Male / epidemiology
  • Breast Neoplasms, Male / genetics
  • Cell Cycle Proteins
  • Codon, Nonsense
  • DNA Mutational Analysis
  • DNA, Neoplasm / genetics
  • DNA-Binding Proteins
  • Female
  • Genes, BRCA1
  • Humans
  • Male
  • Middle Aged
  • Mutation, Missense
  • Neoplasms, Multiple Primary / epidemiology
  • Neoplasms, Multiple Primary / genetics
  • Neoplastic Syndromes, Hereditary / epidemiology
  • Neoplastic Syndromes, Hereditary / genetics*
  • Ovarian Neoplasms / epidemiology
  • Ovarian Neoplasms / genetics*
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / physiology
  • RNA Splicing / genetics
  • Tumor Suppressor Proteins


  • BRCA2 Protein
  • Cell Cycle Proteins
  • Codon, Nonsense
  • DNA, Neoplasm
  • DNA-Binding Proteins
  • Tumor Suppressor Proteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein Serine-Threonine Kinases