What is CHEK2 (Checkpoint Kinase 2) syndrome?

From the Guidelines

CHEK2 syndrome is a hereditary cancer predisposition condition caused by mutations in the CHEK2 gene, which normally functions as a tumor suppressor by regulating cell division and DNA repair, and management typically includes enhanced cancer surveillance with earlier and more frequent screenings, such as annual mammograms and breast MRIs beginning at age 40 (or earlier based on family history) for women, and age-appropriate colorectal cancer screening 1.

Key Points

• People with CHEK2 mutations have an increased risk of developing several types of cancer, most notably breast cancer (approximately 2-3 times higher risk than the general population), but also colorectal, prostate, thyroid, and kidney cancers 1.
• Unlike BRCA mutations, CHEK2 mutations confer a moderate rather than high cancer risk, and cancer risks are strongly influenced by other factors, including family history, non-CHEK2 genetic background, and reproductive and lifestyle factors 1.
• Personalized risk assessment using at least assessment of family history but ideally with a model such as CanRisk is important to consider when making breast cancer surveillance recommendations for CHEK2 heterozygotes with truncating variants 1.
• Risk-reducing medications like tamoxifen may be considered for breast cancer prevention in some cases, and prophylactic surgeries are generally not routinely recommended but may be discussed based on personal and family history 1.

Management

• Enhanced cancer surveillance with earlier and more frequent screenings, such as annual mammograms and breast MRIs beginning at age 40 (or earlier based on family history) for women, and age-appropriate colorectal cancer screening 1.
• Personalized risk assessment using a model such as CanRisk to consider when making breast cancer surveillance recommendations for CHEK2 heterozygotes with truncating variants 1.
• Education on modifiable risk factors for cancer is undertaken, and CRC and PC surveillance should be based on a personalized risk assessment, including family history and other risk factors 1.

Inheritance Pattern

• CHEK2 mutations follow an autosomal dominant inheritance pattern, meaning children of affected individuals have a 50% chance of inheriting the mutation, making genetic counseling important for family members 1.

From the Research

Definition of CHEK2 Syndrome

• CHEK2 syndrome refers to a condition where individuals have a germline mutation in the CHEK2 gene, which encodes the CHK2 kinase protein [(2,3,4,5,6)].
• This mutation can lead to a moderately increased risk of developing certain types of cancer, including breast, prostate, kidney, thyroid, and colon cancer [(2,4,6)].

Cancer Risks Associated with CHEK2 Mutations

• Truncating CHEK2 mutations are associated with a high risk of breast cancer, with an odds ratio (OR) of 8.19 2.
• Missense variants of uncertain significance (VUS) in CHEK2 can also increase the risk of breast cancer, with an OR of 4.06 for functionally deleterious VUS 2.
• Carriers of CHEK2 mutations are also at increased risk of developing other types of cancer, including prostate, kidney, thyroid, and colon cancer [(4,6)].

Clinical Significance of CHEK2 Mutations

• CHEK2 mutations can be inherited in an autosomal dominant pattern, meaning that a single copy of the mutated gene is enough to increase cancer risk [(2,4)].
• The clinical significance of CHEK2 mutations can vary depending on the type and location of the mutation, as well as the individual's family history of cancer [(2,3,5,6)].
• Annual follow-up with breast ultrasound, mammography, or magnetic resonance imaging is recommended for asymptomatic CHEK2 mutation carriers from the age of 40 2.