Heterozygous ATM mutations do not contribute to early onset of breast cancer

M G FitzGerald, J M Bean, S R Hegde, H Unsal, D J MacDonald, D P Harkin, D M Finkelstein, K J Isselbacher, D A Haber, Denis Harkin

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283 Citations (Scopus)


Ataxia telangiectasia (AT) is a recessive syndrome, including cerebellar degeneration, immunologic defects and cancer predisposition, attributed to mutations in the recently isolated ATM (ataxia telangiectasia, mutated) gene. AT is diagnosed in 1/40,000 to 1/100,000 live births, with carriers calculated to comprise approximately 1% of the population. Studies of AT families have suggested that female relatives presumed to be carriers have a 5 to 8-fold increased risk for developing breast cancer, raising the possibility that germline ATM mutations may account for approximately 5% of all breast cancer cases. The increased risk for breast cancer reported for AT family members has been most evident among younger women, leading to an age-specific relative risk model predicting that 8% of breast cancer in women under age 40 arises in AT carriers, compared with 2% of cases between 40-59 years. To test this hypothesis, we undertook a germ-line mutational analysis of the ATM gene in a population of women with early onset of breast cancer, using a protein truncation (PTT) assay to detect chain-terminating mutations, which account for 90% of mutations identified in children with AT. We detected a heterozygous ATM mutation in 2/202 (1%) controls, consistent with the frequency of AT carriers predicted from epidemiologic studies. ATM mutations were present in only 2/401 (0.5%) women with early onset of breast cancer (P = 0.6). We conclude that heterozygous ATM mutations do not confer genetic predisposition to early onset of breast cancer.

Original languageEnglish
Pages (from-to)307-10
Number of pages4
JournalNature Genetics
Issue number3
Publication statusPublished - Mar 1997


  • Adult
  • African Continental Ancestry Group
  • Age of Onset
  • Asian Americans
  • Ataxia Telangiectasia Mutated Proteins
  • Base Sequence
  • Breast Neoplasms
  • Cell Cycle Proteins
  • DNA Primers
  • DNA-Binding Proteins
  • Exons
  • Female
  • Frameshift Mutation
  • Heterozygote Detection
  • Humans
  • Introns
  • Jews
  • Leucine Zippers
  • Middle Aged
  • Point Mutation
  • Polymerase Chain Reaction
  • Protein-Serine-Threonine Kinases
  • Proteins
  • Sequence Deletion
  • Tumor Suppressor Proteins
  • United States


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