Missense variants in ATM in 26,101 breast cancer cases and 29,842 controls

Olivia Fletcher, Nichola Johnson, Isabel dos Santos Silva, Nick Orr, Alan Ashworth, Heli Nevanlinna, Tuomas Heikkinen, Kristiina Aittomäki, Carl Blomqvist, Barbara Burwinkel, Claus R Bartram, Alfons Meindl, Rita K Schmutzler, Angela Cox, Ian Brock, Graeme Elliott, Malcolm W R Reed, Melissa C Southey, Letitia Smith, Amanda B SpurdleJohn L Hopper, Fergus J Couch, Janet E Olson, Xianshu Wang, Zachary Fredericksen, Peter Schürmann, Regina Waltes, Michael Bremer, Thilo Dörk, Peter Devilee, Christie J van Asperen, Rob A E M Tollenaar, Caroline Seynaeve, Per Hall, Kamila Czene, Keith Humphreys, Jianjun Liu, Shahana Ahmed, Alison M Dunning, Melanie Maranian, Paul D P Pharoah, Georgia Chenevix-Trench, Jonathan Beesley, Natalia V Bogdanova, Natalia N Antonenkova, Iosif V Zalutsky, Hoda Anton-Culver, Argyrios Ziogas, Hiltrud Brauch, Yon-Dschun Ko, kConFab Investigators

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)


BACKGROUND: Truncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious.

METHODS: We have genotyped five polymorphic (minor allele frequency, 0.9-2.6%) missense single nucleotide polymorphisms (SNP) in ATM (S49C, S707P, F858L, P1054R, and L1420F) in 26,101 breast cancer cases and 29,842 controls from 23 studies in the Breast Cancer Association Consortium.

RESULTS: Combining the data from all five SNPs, the odds ratio (OR) was 1.05 for being a heterozygote for any of the SNPs and 1.51 for being a rare homozygote for any of the SNPs with an overall trend OR of 1.06 (P(trend) = 0.04). The trend OR among bilateral and familial cases was 1.12 (95% confidence interval, 1.02-1.23; P(trend) = 0.02).

CONCLUSIONS: In this large combined analysis, these five missense ATM SNPs were associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer.

IMPACT: Testing the combined effects of rare missense variants in known breast cancer genes in large collaborative studies should clarify their overall contribution to breast cancer susceptibility.

Original languageEnglish
Pages (from-to)2143-51
Number of pages9
JournalCancer Epidemiology Biomarkers & Prevention
Issue number9
Publication statusPublished - Sep 2010


  • Ataxia Telangiectasia Mutated Proteins
  • Breast Neoplasms
  • Case-Control Studies
  • Cell Cycle Proteins
  • DNA Mutational Analysis
  • DNA-Binding Proteins
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Mutation, Missense
  • Polymorphism, Single Nucleotide
  • Protein-Serine-Threonine Kinases
  • Risk Factors
  • Tumor Suppressor Proteins
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.


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