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Biallelic mutations in the ataxia-telangiectasia mutated (ATM) gene result in ataxia-telangiectasia (A-T). Studies on A-T families have shown that obligate female carriers have increased risk of developing breast cancer. Here we have evaluated the role of known FinnishATMgerm line mutations as possible breast cancer predisposing alleles outside A-T families by analyzing their prevalence in large cohorts of familial and unselected breast cancer cases. Of seven different alterations, two were observed in the studied breast cancer material.ATM6903insA (causing protein truncation) was seen in 3/541 familial and 5/1124 unselected cases, but not among healthy population controls (0/1107). 7570G&gt;C (Ala2524Pro) occurred in 1/541 familial and 2/1124 unselected cases compared with 1/1107 in controls. Additionally, 8734A&gt;G (Arg2912Gly) associated previously with breast cancer susceptibility and suggested to be causative also for A-T was detected in 2/541 of familial cases, but not in unselected cases (0/1124) or controls (0/1107). In total, heterozygousATMmutation carriers were observed in 6/541 familial [P= 0.006, odds ratio (OR) 12.4, 95% confidence interval (CI) 1.5–103.3) and 7/1124 unselected cases (P= 0.07, OR 6.9, 95% CI 0.9–56.4), compared with 1/1107 in controls, suggesting an apparent yet overall limited contribution to predisposition to cancer. The current results also provided evidence for founder effects in the geographical distribution of these mutations. Interestingly, results from functional analysis of the breast cancer-associatedATMmutations indicated that cancer susceptibility is not restricted to mutations with dominant-negative effect on kinase activity, displayed only by 7570G&gt;C, whereas 8734A&gt;G showed only a partial defect in the phosphorylation ofATMsubstrates, and 6903insA seemed to be a null allele.

Evaluation of the role of Finnish ataxia-telangiectasia mutations in hereditary predisposition to breast cancer