Mutations in the ATM gene are the cause of a rare autosomal recessive
syndrome, ataxia-telangiectasia (AT). Of the general population, approximately 0.35-1% has been estimated to be heterozygous for a germline mutation in the ATM gene. The finding that ATM heterozygotes have an increased
breast cancer risk was supported by some studies but not confirmed by others. In our study, the entire coding sequence of the ATM gene was prescreened for mutations by the
protein truncation test to detect the chain-terminating mutations that are highly predominant in patients with AT.
DNA sequencing then characterized 3 (1.9%) pathogenic mutations among 161 high-risk
breast cancer patients. The c.5177+1G>A splicing mutation was a novel gene alteration. No mutation was detected in a group of 183 control individuals. Our results suggest that truncating mutations in ATM increase
breast cancer risk and contribute to inherited
breast cancer. The analysis further uncovered the c.1066-6T>G splicing mutation once among high-risk patients (0.6%) and twice among controls (1.1%) suggesting that this mutation does not confer an increase in
breast cancer risk. On the other hand, individuals heterozygous for this truncating variant displayed loss of exon 11 in approximately 50% of ATM transcripts. Immunohistochemistry did not detect the
ATM protein in the
tumor sample carrying this mutation. Thus, the association of the c.1066-6T>G mutation with
familial breast cancer remains uncertain. Loss of the wild-type ATM allele has not been detected in the
tumor samples from heterozygous carriers of the ATM mutation. Our experiments did not detect the hypermethylation of the ATM promoter in any of the
DNA samples from
tumor tissues.