CHEK2 encodes checkpoint kinase 2 (CHK2), a serine/threonine kinase that plays a critical role in the DNA damage response pathway. CHK2 functions as part of the ATM-CHEK2-p53 axis, which serves as a backbone for DNA damage response to double-strand breaks, though its role in p53-dependent cell cycle arrest is dispensable 1. The protein participates in various cellular processes including DNA repair, cell cycle checkpoints, and apoptosis signaling in response to DNA damage. Functionally, CHK2 phosphorylates downstream targets to coordinate DNA damage responses, with activity dependent on proper folding of its kinase and forkhead-associated domains 2. Germline pathogenic variants in CHEK2 are associated with moderate cancer risk, particularly breast cancer. Protein-truncating variants confer a 3.11-fold increased breast cancer risk, with stronger associations for estrogen receptor-positive disease 3. Functionally deleterious missense variants also significantly increase breast cancer risk (OR=3.90) 4. CHEK2 variants are among the most frequent germline alterations identified in hereditary cancer testing 1. Clinical management requires personalized risk assessment, as cancer risks vary based on family history and other modifiers, with some individuals having risks similar to the general population while others qualify for high-risk surveillance 5.