Constitutional alterations of the ATM gene in early-onset sporadic breast cancer

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Since epidemiological evidence suggests that obligate ataxia telangiectasia (A-T) heterozygotes are at increased risk of developing breast cancer, we have analysed the germline configuration of the ataxia telangiectasia mutated gene (ATM) in 26 premenopausal breast cancer patients with no familial history of breast/ovarian cancer and who developed breast cancer before the age of 40. Five previously undescribed germline sequence variants were detected by SSCP screening of the 66 ATM exons. These included 3 rare variants with an estimated allelic frequency of less than 1%: IVS59-20del4, IVS63+24delTT, and K1454N; 1 rare polymorphism (IVS56+23insT) with an estimated allelic frequency of 2%; and 1 missense mutation F1463C. We considered F1463C as a pathogenic mutation because the same phenylalanine amino acid substituted for a serine at this position is a known A-T mutation. No sequence variant was found in a control group of 45 healthy blood donors. These observations support the hypothesis that constitutional alterations of the ATM gene may contribute to the pathogenesis of some early-onset sporadic breast cancer.