What is CHEK2 Genetic Testing?
CHEK2 genetic testing identifies pathogenic or likely pathogenic variants in the CHEK2 gene, a moderate-penetrance cancer susceptibility gene that increases lifetime risk for breast cancer (20-30%), colorectal cancer, and prostate cancer. 1, 2
Gene Function and Clinical Significance
CHEK2 encodes a checkpoint kinase protein involved in DNA damage response and repair pathways, functioning as a tumor suppressor gene. 1
Pathogenic variants in CHEK2 are found in approximately 0.8-2.2% of hereditary cancer patients, with higher prevalence in breast cancer cohorts (1.3%) and colorectal cancer patients (1.0%). 1, 3
CHEK2 is classified as a moderate-penetrance gene, meaning cancer risks lie on a continuous spectrum from population-level to high-risk depending on the specific variant, family history, and other genetic/non-genetic modifiers. 1, 2
Testing Methodology
CHEK2 testing is typically performed through multigene panel testing that includes other breast cancer susceptibility genes like BRCA1/2, PALB2, and ATM. 1
Testing can be ordered from germline DNA (blood or saliva) or identified incidentally through tumor sequencing, though variants found on tumor testing must be confirmed with germline testing. 1, 2
Common pathogenic variants include c.1100del (protein-truncating), c.1434del, and missense variants like p.(Ile157Thr), with protein-truncating variants conferring higher cancer risk than missense variants. 1, 2
Who Should Be Tested
Individuals with personal history of breast cancer diagnosed at young age (<50 years), particularly with family history of breast or other CHEK2-associated cancers. 1
Individuals with family history of multiple breast cancers, colorectal cancer, or prostate cancer across generations. 1
First-degree relatives (especially sisters and brothers) of known CHEK2 carriers should be offered cascade genetic testing. 1, 2, 4
CHEK2 is NOT included on the ACMG Secondary Findings list for reporting following exome or genome sequencing, as clinical management strategies are less clear when variants are identified outside the context of relevant family history. 1
Cancer Risks Associated with CHEK2 Variants
Breast Cancer
Lifetime breast cancer risk is 20-30% for CHEK2 carriers, with protein-truncating variants conferring higher risk than missense variants. 1, 2
CHEK2-associated breast cancers are predominantly ER-positive (91.5% hormone receptor-positive). 5
For CHEK2 carriers already diagnosed with breast cancer, the 10-year cumulative risk of contralateral breast cancer is 13% in premenopausal women and 4% in postmenopausal women. 2, 4
Colorectal Cancer
- CHEK2 variants confer approximately 2-fold increased risk for colorectal cancer, though absolute risk estimates vary by population and family history. 1
Prostate Cancer
- Male CHEK2 carriers have modestly increased prostate cancer risk, particularly relevant when there is family history of prostate cancer. 1, 2
Other Cancers
CHEK2 variants have been associated with increased risk of pancreatic cancer, kidney cancer, and thyroid cancer, though evidence is less robust than for breast and colorectal cancers. 1
Recent evidence shows CHEK2 variants predispose to myeloid malignancies (myeloproliferative neoplasms, myelodysplastic syndromes) with odds ratios of 2.1-12.3, and chronic lymphocytic leukemia with odds ratio of 14.83. 6
Clinical Management of CHEK2 Carriers
Breast Cancer Surveillance
Annual mammography starting at age 40, or 10 years before the youngest affected relative's diagnosis. 2, 4
Annual breast MRI starting at age 30-35, with combined MRI plus mammography providing 91-98% sensitivity for breast cancer detection. 2, 4
Risk assessment should utilize the CanRisk calculator to incorporate both the CHEK2 variant and family history, as combined risk often exceeds 30% lifetime risk threshold for enhanced surveillance. 1, 2, 4
Colorectal Cancer Surveillance
In the absence of family history of colorectal cancer, follow population-based screening guidelines (colonoscopy starting at age 45-50). 2
With family history of colorectal cancer, earlier and more frequent colonoscopy may be warranted based on country-specific guidelines and family history. 1
Prostate Cancer Screening
- Male CHEK2 carriers, particularly those with family history of prostate cancer, should discuss prostate cancer screening with their healthcare provider. 1, 2
Genetic Counseling Considerations
Pre- and post-test genetic counseling is essential given the complexities of CHEK2 variant interpretation, evolving risk estimates, and limited evidence on surveillance effectiveness. 1
Individuals who test negative for a familial CHEK2 variant still require residual risk assessment (particularly for breast cancer) as predictive testing is more complex for CHEK2 than for high-penetrance genes like BRCA1/2. 1
Predictive genetic testing for familial CHEK2 variants is not routinely recommended in childhood, as cancer risks do not manifest until adulthood. 1
Critical Pitfalls to Avoid
Do not rely solely on family history from one side of the family—CHEK2 variants can be inherited from the side without apparent cancer history. 1, 2
Do not dismiss missense variants entirely—while variants like p.(Ile157Thr) alone may not change management, combined with family history they significantly elevate risk. 1, 2
Do not assume germline status from tumor testing alone—variants found on tumor sequencing must be confirmed with germline testing. 1, 2
Do not confuse variant pathogenicity with disease penetrance—some laboratories report variants as "pathogenic (low penetrance)" or "moderate risk variant," reflecting that the variant is disease-causing but confers moderate rather than high cancer risk. 1
Variant Interpretation Challenges
Common variants like c.1100del are well-established as pathogenic, but many rare missense variants remain variants of uncertain significance (VUS). 1, 3
Bioinformatics analysis, cosegregation studies, and functional assays can help reclassify VUS, though this remains an active area of research. 3, 7
Some variants (like p.(Ile157Thr)) have conflicting interpretations in ClinVar, with some laboratories reporting as VUS and others as pathogenic with low penetrance. 1