The ATM missense mutation p.Ser49Cys (c.146C>G) and the risk of breast cancer

Hum Mutat. 2006 Jun;27(6):538-44. doi: 10.1002/humu.20323.


Homozygous mutation in the ATM gene causes ataxia telangiectasia and heterozygous mutation carriers may be at increased risk of breast cancer. We studied a total of 22 ATM variants; 18 variants were analyzed in one of two large population-based studies from the U.S. and Poland, and four variants were analyzed in all 2,856 breast cancer cases and 3,344 controls from the two studies. The missense mutation Ser49Cys (c.146C>G, p.S49C), carried by approximately 2% of subjects, was more common in cases than controls in both study populations, combined odds ratio (OR) 1.69 (95% CI, 1.19-2.40; P=0.004). Another missense mutation at approximately 2% frequency, Phe858Leu (c.2572T>C, p.F858L), was associated with a significant increased risk in the U.S. study but not in Poland, and had a combined OR of 1.44 (95% CI, 0.98-2.11; P=0.06). These analyses provide the most convincing evidence thus far that missense mutations in ATM, particularly p.S49C, may be breast cancer susceptibility alleles. Because of their low frequency, even larger sample sizes are required to more firmly establish these associations.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Ataxia Telangiectasia Mutated Proteins
  • Breast Neoplasms / epidemiology
  • Breast Neoplasms / genetics*
  • Case-Control Studies
  • Cell Cycle Proteins / genetics*
  • DNA-Binding Proteins / genetics*
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Middle Aged
  • Mutation, Missense*
  • Poland / epidemiology
  • Protein-Serine-Threonine Kinases / genetics*
  • Risk Factors
  • Tumor Suppressor Proteins / genetics*
  • United States / epidemiology


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