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Title: Missense variants in ATM in 26,101 breast cancer cases and 29,842 controls.
Authors: Fletcher O,  Johnson N,  dos Santos Silva I,  Orr N,  Ashworth A,  Nevanlinna H,  Heikkinen T,  Aittomäki K,  Blomqvist C,  Burwinkel B,  Bartram CR,  Meindl A,  Schmutzler RK,  Cox A,  Brock I,  Elliott G,  Reed MW,  Southey MC,  Smith L,  Spurdle AB,  Hopper JL,  Couch FJ,  Olson JE,  Wang X,  Fredericksen Z,  Schürmann P,  Waltes R,  Bremer M,  Dörk T,  Devilee P,  van Asperen CJ,  Tollenaar RA,  Seynaeve C,  Hall P,  Czene K,  Humphreys K,  Liu J,  Ahmed S,  Dunning AM,  Maranian M,  Pharoah PD,  Chenevix-Trench G,  kConFab Investigators,  AOCS Group,  Beesley J,  Bogdanova NV,  Antonenkova NN,  Zalutsky IV,  Anton-Culver H,  Ziogas A,  Brauch H,  Ko YD,  Hamann U,  GENICA Consortium,  Fasching PA,  Strick R,  Ekici AB,  Beckmann MW,  Giles GG,  Severi G,  Baglietto L,  English DR,  Milne RL,  Benítez J,  Arias JI,  Pita G,  Nordestgaard BG,  Bojesen SE,  Flyger H,  Kang D,  Yoo KY,  Noh DY,  Mannermaa A,  Kataja V,  Kosma VM,  García-Closas M,  Chanock S,  Lissowska J,  Brinton LA,  Chang-Claude J,  Wang-Gohrke S,  Broeks A,  Schmidt MK,  van Leeuwen FE,  Van't Veer LJ,  Margolin S,  Lindblom A,  Humphreys MK,  Morrison J,  Platte R,  Easton DF,  Peto J,  Breast Cancer Association Consortium
Journal: Cancer Epidemiol Biomarkers Prev
Date: 2010 Sep
Branches: MEB, LTG, CGR
PubMed ID: 20826828
PMC ID: PMC2938473
Abstract: 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.