title: Two ATM variants and breast cancer risk.
abstract: The ATM gene is mutated in ataxia-telangiectasia (AT). Heterozygote female relatives of AT cases have a 2-7fold increased risk of breast cancer. We previously reported high risks of breast cancer associated with certain ATM variants. To estimate the risks more precisely, we have examined two ATM variants, c.1066-6T>G (IVS10-6T>G) and c.4258C>T (p.Leu1420Phe), in additional cases and controls from the same Australian cohorts previously used to estimate the risk of breast cancer associated with c.1066-6T>G. A total of 775 and 84 population-based controls were genotyped for the c.1066-6T>G and c.4258C>T ATM variants respectively, as were index cases from 378 and 373 non-BRCA1/2 breast cancer families. Penetrance was estimated by Bayes factor analysis. The allele frequencies of ATM c.1066-6T>G and c.4258C>T estimated from controls were 0.005 (95% CI=0.002 to 0.009) and 0.012 (95% CI=0.001 to 0.042), respectively. We identified three new breast cancer families with c.1066-6T>G, and seven families with c.4258C>T. Combining with the two c.1066-6T>G families previously reported, the estimated penetrance to age 70 of c.1066-6T>G was 17.2% (95% CI=4.7% to 37.5%). For c.4258C>T, the estimated average penetrance was 4.8% (95% CI 1.7% to 10.1%). In conclusion, we found no evidence that the ATM c.4258C>T variant increases breast cancer risk, and little evidence that c.1066-6T>G confers an elevated risk. Analysis of additional families will be necessary to define more precisely the risk, if any, associated with c.1066-6T>G.
authors.affiliation: Cancer Research United Kingdom Genetic Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Deborah
authors.initials: D
authors.lastname: Thompson
authors.forename: Antonis C
authors.initials: AC
authors.lastname: Antoniou
authors.forename: Mark
authors.initials: M
authors.lastname: Jenkins
authors.forename: Anna
authors.initials: A
authors.lastname: Marsh
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Chen
authors.forename: Tierney
authors.initials: T
authors.lastname: Wayne
authors.forename: Andrea
authors.initials: A
authors.lastname: Tesoriero
authors.forename: Roger
authors.initials: R
authors.lastname: Milne
authors.forename: Amanda
authors.initials: A
authors.lastname: Spurdle
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Thorstenson
authors.forename: Melissa
authors.initials: M
authors.lastname: Southey
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.forename: Kum Kum
authors.initials: KK
authors.lastname: Khanna
authors.forename: Joseph
authors.initials: J
authors.lastname: Sambrook
authors.forename: Peter
authors.initials: P
authors.lastname: Oefner
authors.forename: David
authors.initials: D
authors.lastname: Goldgar
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Doug
authors.initials: D
authors.lastname: Easton
authors.forename: Georgia
authors.initials: G
authors.lastname: Chenevix-Trench
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D001499:Bayes Theorem; D001943:Breast Neoplasms / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D009154:Mutation / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases