What are the screening and prevention recommendations for an individual with a pathologic CHEK2 (Checkpoint Kinase 2) mutation?

Management of Pathologic CHEK2 Mutation

Individuals with pathogenic CHEK2 mutations require enhanced breast cancer surveillance with annual mammography starting at age 40 (or 10 years before the youngest affected relative), annual breast MRI starting at age 30-35, and cascade genetic testing of first-degree relatives, particularly female siblings. 1, 2

Breast Cancer Surveillance

Risk Quantification

• CHEK2 carriers have a 20-30% lifetime breast cancer risk, with protein-truncating variants conferring higher risk than missense variants 2, 3
• Risk assessment should utilize CanRisk calculator to incorporate both the CHEK2 variant and family history, as combined risk often exceeds 30% 1
• Homozygous CHEK2*1100delC carriers have a >100-fold increased risk compared to non-carriers, warranting the most intensive surveillance 4

Screening Protocol

For women with CHEK2 pathogenic variants:

• Age 30-35: Begin annual breast MRI 2
• Age 40: Add annual mammography (preferably digital breast tomosynthesis) to continue alongside MRI 2
• Alternative timing: Start mammography 10 years before the youngest affected relative's diagnosis if earlier than age 40 2
• MRI plus mammography combined achieves 91-98% sensitivity and reduces breast cancer mortality by >50% in high-risk women 2

Important Caveats

• Country-specific definitions of "high risk" vary, so surveillance intensity should follow local guidelines while incorporating the CHEK2 status 1
• Digital breast tomosynthesis (DBT) is preferred over standard mammography as it decreases recall rates and improves cancer detection 2
• Continue screening indefinitely as long as life expectancy exceeds 10 years 2

Contralateral Breast Cancer Risk

For CHEK2 carriers already diagnosed with breast cancer:

• Premenopausal women: 13% 10-year cumulative risk of contralateral breast cancer 1
• Postmenopausal women: 4% 10-year cumulative risk of contralateral breast cancer 1
• CHEK2 heterozygotes with breast cancer have a 2-fold increased risk (HR 2.0-2.25) of developing contralateral breast cancer 1

Colorectal Cancer Surveillance

• In the absence of family history of colorectal cancer, follow population-based screening guidelines (typically colonoscopy at age 45-50) 1
• The missense I157T variant may confer a modest 1.5-fold increased colorectal cancer risk, but protein-truncating variants do not appear to increase colorectal cancer risk 5
• If there is a family history of colorectal cancer, intensify surveillance accordingly, though specific CHEK2-related protocols are not established 1

Prostate Cancer Considerations

• CHEK2 mutations are associated with increased prostate cancer risk 3
• Male relatives, particularly brothers, should be offered genetic testing especially if there is family history of prostate cancer 1
• Prostate cancer surveillance should be discussed with male carriers, though specific protocols are not definitively established in the guidelines provided

Cascade Genetic Testing

First-degree relatives should be offered genetic testing:

• Sisters are the highest priority given the substantial breast cancer risk 1
• Brothers should be tested, particularly if there is family history of prostate cancer 1
• Parents and children should be counseled about testing options 1

Variant-Specific Considerations

Common Variants

• CHEK2*1100delC (protein-truncating): Most well-studied, confers 2-4 fold breast cancer risk in heterozygotes 3
• I157T (missense): Lower penetrance, may not warrant management changes in isolation without family history 1

Rare Variants

• Large duplications and other rare variants can confer high cancer susceptibility and should be managed similarly to truncating mutations 6
• Tumor sequencing may help clarify whether a CHEK2 variant is implicated in tumorigenesis 1

Key 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
• Do not dismiss missense variants entirely—while I157T alone may not change management, combined with family history it significantly elevates risk 1
• Do not assume germline status from tumor testing alone—variants found on tumor sequencing should be confirmed with germline testing 1
• Do not use polygenic risk scores as standard of care yet—while they may modify risk estimates, they require additional validation 1