ATM missense mutations are frequent in patients with breast cancer.

Ataxia telangiectasia (A-T), an autosomal recessive neuro-immunologic disease with cancer susceptibility, results from ATM gene mutations. Most mutations in A-T patients cause protein truncation. Epidemiologic evidence suggests that ATM gene mutation carriers may be at increased risk for breast cancer, but the protein-truncating mutations that compose the majority of mutations in patients with ataxia telangiectasia are not elevated in women with breast cancer. In this report we present evidence that missense mutations in the ATM gene predispose to breast cancer. The analysis was performed in two phases in a total of 90 women with breast cancer and 90 ethnically similar control individuals. DOVAM-S, a robotically enhanced multiplexed, highly redundant form of SSCP in which virtually all mutations within the input amplicons can be detected, was used to scan all the coding exons and flanking splice junctions. Cohort-specific mutations were significantly elevated in women with breast cancer in phase 1 (43 cases) and phase 2 (47 cases). For the 90 patients and 90 controls, total missense mutations were significantly elevated in cases [OR=2.0; 90% CI=1.01-4.15]. Cohort-specific missense variants displayed an odds ratio of 4.0 (90% CI=1.37-13.5). It is estimated that the attributable risk of mutations in the ATM gene is 13% in this cohort of women with breast cancer.