ATM encodes a kinase that acts as a master controller of the cellular DNA damage response: it detects double-strand breaks and coordinates DNA repair, cell cycle arrest, or apoptosis through downstream targets including p53, BRCA1, and CHK2. Loss-of-function mutations in both copies of ATM cause ataxia telangiectasia, an autosomal recessive disorder characterized by neurological problems, immune deficiency, and cancer predisposition. ATM functions as a tumor suppressor: individuals with ataxia telangiectasia are prone to childhood lymphomas, leukemias, and breast cancer, while carriers of a single altered copy have increased risk of breast, pancreatic, prostate, and other cancers. Somatic ATM mutations also occur in lymphoid malignancies and solid tumors, and ATM-deficient cancers are often especially sensitive to DNA-damaging treatments.

ATM is a tumor suppressor: biallelic loss of function causes ataxia telangiectasia, and monoallelic loss raises the risk of breast, pancreatic, and other cancers. This p.Asp851Gly missense variant is classified as a VUS because the only VCEP-qualifying evidence, a low REVEL score (0.099) consistent with a benign effect, is too weak to establish it as benign or pathogenic. As a VUS, it should not by itself be used to assign ATM-related cancer risk or to guide DNA-damaging cancer treatment decisions.