About this condition
CHEK2 (Hereditary Cancer Risk)
CHEK2 encodes checkpoint kinase 2, a serine/threonine kinase activated by ATM in response to DNA damage. Once activated, CHEK2 phosphorylates critical cell cycle regulators including p53 and BRCA1, coordinating DNA repair, cell cycle arrest, and apoptosis. Pathogenic CHEK2 variants impair this checkpoint function, allowing damaged cells to continue dividing unchecked. The most studied variant, c.1100delC, produces a truncated, unstable protein. Pathogenic CHEK2 variants are classified as moderate-penetrance — conferring approximately 2–3-fold increased breast cancer risk (lifetime risk ~20–30%), with risk stratified by family history.
CHEK2 is more common in the population than BRCA1/2 — the c.1100delC variant has a carrier frequency of 0.2–1.4% in European populations. Beyond breast cancer, CHEK2 variants are associated with modestly increased risk of prostate, colorectal, kidney, thyroid, and hematological cancers. Biallelic CHEK2 carriers (rare) have substantially higher breast cancer risk than monoallelic carriers. The challenge is that clinical guidelines for CHEK2 management are less established than for BRCA1/2, historically creating provider uncertainty.
A CHEK2 pathogenic variant finding has immediate clinical implications. It explains the hereditary breast cancer pattern in families that tested BRCA-negative — a finding that occurs in approximately 5% of such families. It qualifies carriers for enhanced breast MRI surveillance starting at age 40 (or earlier with family history). For males, it enables prostate cancer awareness and early screening discussion. Cascade testing of first-degree relatives identifies additional carriers who benefit from surveillance, converting one person's genetic discovery into family-wide preventive opportunities.
- Gene locus
- CHEK2 (22q12.1)
