What are the recommended cancer screening guidelines for a patient with the CHEK2 (Checkpoint Kinase 2) c.592+3A>T mutation?

CHEK2 c.592+3A>T Management

The CHEK2 c.592+3A>T variant is a splice-site mutation that requires enhanced breast cancer surveillance with annual mammography starting at age 40 and annual breast MRI starting at age 30-35, with screening intensity guided by CanRisk assessment incorporating both the mutation and family history. 1, 2

Variant Classification and Clinical Significance

The c.592+3A>T variant is a splice-donor mutation affecting the canonical splice site, similar to the c.1461+1G>T variant described in ACMG guidelines, which is classified as likely pathogenic. 3 Splice-site variants in CHEK2 typically disrupt normal protein function and confer moderate breast cancer risk, though penetrance varies based on family history. 4

Breast Cancer Surveillance Protocol

Risk Stratification

• Use the CanRisk calculator to determine individualized lifetime breast cancer risk by incorporating the CHEK2 variant, family history, and other risk factors—combined risk frequently exceeds 30%. 1, 2
• Baseline lifetime breast cancer risk for CHEK2 carriers ranges from 20-30%, but this increases substantially with positive family history: 20% with no affected relatives, 28% with one second-degree relative, 34% with one first-degree relative, and 44% with both first- and second-degree relatives affected. 4

Screening Recommendations

• Begin annual breast MRI at age 30-35, which provides 91-98% sensitivity for breast cancer detection in high-risk women. 1, 2
• Add annual mammography at age 40 (or 10 years before the youngest affected relative's diagnosis, whichever is earlier), preferably using digital breast tomosynthesis (DBT) to decrease recall rates and improve cancer detection. 2
• Continue combined MRI and mammography screening indefinitely as long as the patient remains in good health with >10 year life expectancy. 2
• The combination of MRI plus mammography reduces breast cancer mortality by more than 50% in CHEK2 carriers. 2

Colorectal Cancer Surveillance

• In the absence of family history of colorectal cancer, follow population-based screening guidelines with colonoscopy starting at age 45-50. 3, 1
• Do not intensify colorectal screening based solely on the CHEK2 mutation without supporting family history. 3

Cascade Genetic Testing

• Test all first-degree relatives, prioritizing sisters given the substantial breast cancer risk (20-44% lifetime risk depending on family history). 1
• Test brothers, particularly if there is family history of prostate cancer, as male CHEK2 carriers have elevated prostate cancer risk. 3, 1
• The risk of specific cancers in CHEK2 carriers is highly dependent on family history—relatives of breast cancer probands have 3.6-fold higher breast cancer risk, while relatives of prostate cancer probands have 4.4-fold higher prostate cancer risk. 5

Critical Pitfalls to Avoid

• Do not assume the mutation came from the side of the family with cancer history—CHEK2 variants are frequently inherited from the side without apparent cancer history. 3, 1
• Do not rely on tumor sequencing alone—if this variant is found on tumor testing, confirm germline status with blood-based genetic testing. 3, 1
• Do not ignore family history from both sides of the pedigree—maternal family history of breast cancer further increases risk even if the CHEK2 variant was inherited paternally. 3
• Do not use the same screening protocol for all CHEK2 carriers—risk stratification with CanRisk is essential because combined risk varies dramatically (20-44%) based on family history. 1, 4

Contralateral Breast Cancer Risk (If Already Diagnosed)

• 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. 1
• CHEK2 heterozygotes with breast cancer have a 2-fold increased risk (HR 2.0) of developing contralateral breast cancer compared to non-carriers. 3, 1

Prognosis

• Survival outcomes for breast cancer patients with CHEK2 mutations are similar to those without mutations, with 10-year survival of approximately 78.8% for CHEK2 carriers versus 80.1% for non-carriers. 6