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The 1100delC mutation of the cell cycle checkpoint kinase 2 (CHEK2) gene confers an increased risk for breast cancer, but the clinical impact of otherCHEK2gene variants remains unclear. We determined the frequency of two functionally relevantCHEK2gene mutations, I157T and IVS2+1G > A, in two large series of breast cancer cases and controls from two independent populations. Our first series consisted of a hospital-based cohort of 996 German breast cancer cases and 486 population controls, and the second series consisted of 424 breast cancer patients and 307 population controls from the Republic of Belarus. The missense substitution I157T was identified in 22/996 cases (2.2%)vs.3/486 controls (0.6%; OR = 3.6, 95% CI 1.1–12.2,p= 0.044) in the German population and in 24/424 cases (5.7%)vs.4/307 controls (1.3%; OR = 4.5, 95% CI 1.6–13.2,p= 0.005) in the Byelorussian cohorts. The splicing mutation IVS2+1G > A was infrequent in both populations, being observed in 3/996 German and 4/424 Byelorussian patients (0.3% and 0.9%, respectively) and in 1/486 German controls (0.2%; adjusted OR = 4.0, 95% CI 0.5–30.8,p= 0.273). HeterozygousCHEK2mutation carriers tended to be diagnosed at an earlier age in both populations, but these differences did not reach statistical significance. Family history of breast cancer did not differ between carriers and noncarriers. Our data indicate that the I157T allele, and possibly the IVS2+1G > A allele, of theCHEK2gene contribute to inherited breast cancer susceptibility.