IVS10-6T>G, an ancient ATM germline mutation linked with breast cancer

Patients with autosomal recessive multisystemic disorder ataxia-telangiectasia are homozygous or compound heterozygous for mutations in the ataxia-telangiectasia mutated (ATM) gene. Heterozygous carriers of an ATM germline mutation have an increased susceptibility for breast cancer. The subject of this study is one particular germline mutation, the ATM exon 11 splice-site mutation IVS10-6T>G, that has been identified as being associated with an increased risk for breast cancer both in the general population and in high-risk breast cancer families. We investigated the natural history of this mutation, i.e., whether it is frequently arising de novo in a population, or whether it can be traced back to a single ancient mutational event. Genotyping of a number of polymorphic markers (two extragenic and two intragenic microsatellite loci, a single nucleotide insertion/deletion polymorphism, and a dinucleotide insertion/deletion polymorphism) was performed in 18 samples from different populations carrying the IVS10-6T>G mutation (17 unrelated breast cancer patients who were heterozygous carriers of this mutation and a single A-T patient who was homozygous for the IVS10-6T>G mutation). The same markers were also genotyped among 39 unrelated healthy individuals without this mutation. Haplotype analyses revealed one common ancestor in all mutation carriers. By means of a maximum likelihood method, we estimated the age of this mutation to be approximately 2,000 generations. We provide evidence that the IVS10-6T>G mutation occurred only once during human evolution, at least 50,000 years ago. Our results predict that this mutation could be widely distributed across Europe and, probably, the Middle East and Western Asia.