Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T > G and c.1066-6T > G (IVS10-6T > G) from the breast cancer family registry Journal Article


Authors: Bernstein, J. L.; Teraoka, S.; Southey, M. C.; Jenkins, M. A.; Andrulis, I. L.; Knight, J. A.; John, E. M.; Lapinski, R.; Wolitzer, A. L.; Whittemore, A. S.; West, D.; Seminara, D.; Olson, E. R.; Spurdle, A. B.; Chenevix-Trench, G.; Giles, G. G.; Hopper, J. L.; Concannon, P.
Article Title: Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T > G and c.1066-6T > G (IVS10-6T > G) from the breast cancer family registry
Abstract: The ATM gene variants segregating in ataxia-telangiectasia families are associated with increased breast cancer risk, but the contribution of specific variants has been difficult to estimate. Previous small studies suggested two functional variants, c.7271T > G and c.1066-6T > G (IVS10-6T > G), are associated with increased risk. Using population-based blood samples we found that 7 out of 3,743 breast cancer cases (0.2%) and 0 out of 1,268 controls were heterozygous for the c.7271T > G allele (P = 0.1). In cases, this allele was more prevalent in women with an affected mother (odds ratio [OR] = 5.5, 95% confidence interval [CI] = 1.2-25.5; P = 0.04) and delayed child-bearing (OR = 5.1; 95% CI = 1.0-25.6; P = 0.05). The estimated cumulative breast cancer risk to age 70 years (penetrance) was 52% (95% CI = 28-80%; hazard ratio [HR] = 8.6; 95% CI = 3.9-18.9; P <0.0001). In contrast, 13 of 3,757 breast cancer cases (0.3%) and 10 of 1,268 controls (0.8%) were heterozygous for the c.1066-6T > G allele (OR = 0.4; 95% CI = 0.2-1.0; P = 0.05), and the penetrance was not increased (P = 0.5). These findings suggest that although the more common c.1066-6T > G variant is not associated with breast cancer, the rare ATM c.7271T > G variant is associated with a substantially elevated risk. Since c.7271T > G is only one of many rare ATM variants predicted to have deleterious consequences on protein function, an effective means of identifying and grouping these variants is essential to assess the contribution of ATM variants to individual risk and to the incidence of breast cancer in the population.
Keywords: adolescent; adult; controlled study; aged; middle aged; major clinical study; case-control studies; dna-binding proteins; cancer risk; cancer incidence; protein function; cell cycle proteins; allele; dna damage; gene; genetic predisposition to disease; breast cancer; incidence; risk factors; breast neoplasms; genetics, population; registries; protein-serine-threonine kinases; tumor suppressor proteins; carcinoma; cancer registry; australia; linkage (genetics); penetrance; ataxia telangiectasia; segregation analysis; atm gene; variation (genetics); ontario; san francisco; atm gene variants
Journal Title: Human Mutation
Volume: 27
Issue: 11
ISSN: 1059-7794
Publisher: Wiley Liss  
Date Published: 2006-11-01
Start Page: 1122
End Page: 1128
Language: English
DOI: 10.1002/humu.20415
PUBMED: 16958054
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 25" - "Export Date: 4 June 2012" - "CODEN: HUMUE" - "Source: Scopus"
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  1. Jonine L Bernstein
    104 Bernstein