Cancer risk in ATM heterozygotes: a model of phenotypic and mechanistic differences between missense and truncating mutations

The failure to find an increased frequency of ATM mutations in large cancer cohorts, especially breast cancer, is contrary to what was anticipated based on the increased cancer susceptibility of obligate ATM heterozygotes from families with ataxia-telangiectasia (A-T). We hypothesize that this paradox might be resolved if two types of ATM heterozygotes exist and the phenotypes differ, i.e., those with truncating types of mutations (ATM(trunc)), that make no protein, and those with missense types of mutations (ATM(mis)), that make reduced amounts of defective protein. The phenotype of ATM(trunc/trunc) mutations is the A-T syndrome; the phenotype of ATM(mis/mis) mutations, judging from the few homozygous patients that have been documented, appears to include some neurological features and cancer susceptibility but not the A-T syndrome. Evidence is reviewed which suggests that ATM(mis/wt) mutations are technically more difficult to detect than ATM(trunc/wt) mutations. Despite this, most large cancer cohort studies have identified mainly missense mutations and few truncating mutations. This model would require a paradigm shift for cancer risk analyses, to recognize the existence of different allele frequencies for the two types of A-T heterozygotes.