A–T, such as the parents of a person with A–T, have one mutated copy of the ATM gene and one normal copy. They are generally healthy, but there is an increased risk of breast cancer in women. This finding has been confirmed in a variety of different ways, and is the subject of current research. Standard surveillance (including monthly breast self-exams and mammography at the usual schedule for age) is recommended, unless additional tests are indicated because the individual has other risk factors (e.g., family history of breast cancer). Pathophysiology How loss of the ATM protein creates a multisystem disorder A–T has been described as a genome instability syndrome, a DNA repair disorder and a DNA damage response (DDR) syndrome. ATM, the gene responsible for this multi-system disorder, encodes a protein of the same name which coordinates the cellular response to DNA double strand breaks (DSBs). Radiation therapy, chemotherapy that acts like radiation (radiomimetic drugs) and certain biochemical processes and metabolites can cause DSBs. When these breaks occur, ATM stops the cell from making new DNA (cell cycle arrest) and recruits and activates other proteins to repair the damage. Thus, ATM allows the cell to repair its DNA before the completion of cell division. If DNA damage is too severe, ATM will mediate the process of programmed cell death (apoptosis) to eliminate the cell and prevent genomic instability. Cancer and radiosensitivity In the absence of the ATM protein, cell-cycle check-point regulation and programmed cell death in response to DSBs are defective. The result is genomic instability which can lead to the development of cancers. Irradiation and radiomimetic compounds induce DSBs which are unable to be repaired appropriately when ATM is absent. Consequently, such agents can prove especially cytotoxic to A–T cells and people with A–T. Delayed pubertal development (gonadal dysgenesis) Infertility is often described as a characteristic of A–T. Whereas this is certainly the case for the mouse model of A–T, in humans it may be more accurate to characterize the reproductive abnormality as gonadal atrophy or dysgenesis characterized by delayed pubertal development. Because programmed DSBs are generated to initiate genetic recombinations involved in the production of sperm and eggs in reproductive organs (a process known as meiosis), meiotic defects and arrest can occur when ATM is not present. Immune system defects and immune-related cancers As lymphocytes develop from stem cells in the bone marrow into mature lymphocytes in the