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Rare variants in the ATM gene and risk of breast cancer

David E Goldgar1, Sue Healey2, James G Dowty3, Leonard Da Silva4, Xiaoqing Chen2, Amanda B Spurdle2, Mary Beth Terry5, Mary J Daly6, Saundra M Buys7, Melissa C Southey8, Irene Andrulis9, Esther M John10, BCFR1035679, kConFab11, Kum Kum Khanna2, John L Hopper3, Peter J Oefner12, Sunil Lakhani134 and Georgia Chenevix-Trench2*

Author Affiliations

1 Department of Dermatology, University of Utah School of Medicine, 30 N. 1900 E, Salt Lake City, UT 84132-2101, USA

2 Queensland Institute of Medical Research, 300 Herston Road, Herston, QLD 4006, Australia

3 Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Grattan Street, Parkville, VIC 3010, Australia

4 University of Queensland Centre for Clinical Research and School of Medicine, Building 71/918 RBWH Bowen Bridge Road, Herston, QLD 4029, Australia

5 Department of Epidemiology, Columbia University, 630 West 168th St, Box 49, New York, NY 10032, USA

6 Fox Chase Cancer Center, 33 Cottman Ave/100 Laurel Avenue, Philadelphia, PA 19111, USA

7 Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112, USA

8 Department of Pathology, University of Melbourne, Grattan Street, Parkville, VIC 3010, Australia

9 Cancer Care Ontario, Fred A. Litwin Center for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 620 University Avenue, Toronto, Ontario M5G, Canada

10 Cancer Prevention Institute of California, 2201 Walnut Avenue, Suite 300, Fremont, CA 94538, USA

11 The Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC 3002, Australia

12 Institute of Functional Genomics, University of Regensburg, Josef-Engert-Str.9, 93053, Regensburg, Germany

13 The Royal Brisbane & Women's Hospital, Cnr Butterfield St and Bowen Bridge Rd, Herston, QLD 4029, Australia

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Breast Cancer Research 2011, 13:R73  doi:10.1186/bcr2919

Published: 25 July 2011



The ataxia-telangiectasia mutated (ATM) gene (MIM ID 208900) encodes a protein kinase that plays a significant role in the activation of cellular responses to DNA double-strand breaks through subsequent phosphorylation of central players in the DNA damage-response pathway. Recent studies have confirmed that some specific variants in the ATM gene are associated with increased breast cancer (BC) risk. However, the magnitude of risk and the subset of variants that are pathogenic for breast cancer remain unresolved.


To investigate the role of ATM in BC susceptibility, we studied 76 rare sequence variants in the ATM gene in a case-control family study of 2,570 cases of breast cancer and 1,448 controls. The variants were grouped into three categories based on their likely pathogenicity, as determined by in silico analysis and analyzed by conditional logistic regression. Likely pathogenic sequence variants were genotyped in 129 family members of 27 carrier probands (15 of which carried c.7271T > G), and modified segregation analysis was used to estimate the BC penetrance associated with these rare ATM variants.


In the case-control analysis, we observed an odds ratio of 2.55 and 95% confidence interval (CI, 0.54 to 12.0) for the most likely deleterious variants. In the family-based analyses, the maximum-likelihood estimate of the increased risk associated with these variants was hazard ratio (HR) = 6.88 (95% CI, 2.33 to 20.3; P = 0.00008), corresponding to a 60% cumulative risk of BC by age 80 years. Analysis of loss of heterozygosity (LOH) in 18 breast tumors from women carrying likely pathogenic rare sequence variants revealed no consistent pattern of loss of the ATM variant.


The risk estimates from this study suggest that women carrying the pathogenic variant, ATM c.7271T > G, or truncating mutations demonstrate a significantly increased risk of breast cancer with a penetrance that appears similar to that conferred by germline mutations in BRCA2.