Management of Variants of Uncertain Significance in Ovarian Cancer
Core Management Principle
Patients with a VUS in BRCA1/BRCA2 genes should NOT be managed as mutation carriers—cancer risk assessment and management decisions must be based solely on personal and family history, not on the VUS result. 1
The presence of a VUS does not establish elevated cancer risk and should be treated as an uninformative genetic test result. 1
Clinical Management Algorithm
Risk Assessment Independent of VUS
Base all cancer risk estimates exclusively on family history criteria, ignoring the VUS finding entirely when calculating risk or making screening recommendations. 1
Apply standard familial risk assessment tools (e.g., Tyrer-Cuzick, BRCAPRO) using only the pedigree structure, ages of onset, and cancer types in relatives—do not input the VUS as a positive finding. 1
For patients with no significant family history, manage according to population-based screening guidelines, as the VUS provides no additional risk information. 1
Surveillance and Prevention Decisions
Do NOT recommend risk-reducing bilateral salpingo-oophorectomy (BSO) based on VUS status, even in patients with ovarian cancer, unless family history alone justifies this intervention. 1
Do NOT implement intensified breast surveillance protocols (e.g., annual breast MRI, alternating mammography/MRI every 6 months) based solely on VUS findings. 1
If the patient already has ovarian cancer, treatment decisions regarding PARP inhibitors should follow standard clinical and tumor testing protocols, not germline VUS status. 2
Genetic Counseling Requirements
Pre-Test and Post-Test Counseling
Explicitly explain during pre-test counseling that VUS results are possible (occurring in 5-20% of tests depending on ethnicity) and that such results cannot guide medical management. 1
Emphasize that most VUS are eventually reclassified as benign (not pathogenic), making premature intervention potentially harmful. 1
Document clearly in the medical record that the VUS should not influence clinical decisions to prevent mismanagement by other providers who may misinterpret the result. 1
Family Testing Restrictions
Do NOT offer predictive genetic testing to at-risk relatives for the VUS, as this provides no clinically useful information and may cause unnecessary anxiety. 1
Testing relatives is only appropriate for variant reclassification purposes (segregation analysis), not for clinical risk assessment, and should be coordinated through genetics specialists. 1
Variant Reclassification Strategy
Active Reclassification Efforts
Establish a recontact system with the testing laboratory to receive updates every 1-2 years, as VUS may be reclassified as additional evidence accumulates. 1
Refer to clinical genetics services for potential enrollment in research studies or variant reclassification programs (e.g., ENIGMA consortium). 1
If affected family members exist, coordinate segregation studies through genetics specialists to determine if the VUS tracks with disease in the family. 1
Evidence That May Reclassify VUS
Multifactorial likelihood analysis incorporating tumor pathology (e.g., triple-negative breast cancer, high-grade serous ovarian cancer), family segregation data, functional assays, and computational predictions can upgrade VUS to Class 4 (likely pathogenic) or downgrade to Class 2 (likely benign). 1
The IARC 5-tier classification system (Class 1-5) provides standardized probability thresholds: Class 3 VUS (0.05-0.949 probability of pathogenicity) requires additional evidence before clinical action. 1
Critical Pitfalls to Avoid
Common Mismanagement Scenarios
NEVER treat VUS as equivalent to pathogenic mutations when counseling patients about prophylactic surgery—this is the most common and harmful error. 1
Avoid cascade testing of family members until the variant is definitively reclassified, as this creates a cascade of uninformative results and psychological distress. 1
Do not assume that finding a VUS in a patient with ovarian cancer means the variant caused the cancer—this cognitive bias ("what is the chance this is coincidental?") leads to overestimation of pathogenicity. 1
Documentation and Communication
Ensure non-genetics clinicians understand that VUS results require genetics consultation before any management decisions, as genetic literacy varies widely among oncologists. 1
In the 22% of VUS cases where oncologists fail to refer to genetics services (as observed in mainstreamed testing programs), proactive genetics consultation should be mandated by institutional protocols. 2
When VUS Is Reclassified
If Upgraded to Pathogenic/Likely Pathogenic
Immediately implement full high-risk management guidelines including consideration of risk-reducing BSO (typically after childbearing completion or by age 35-40 for BRCA1, 40-45 for BRCA2). 1
Offer predictive testing to at-risk relatives and provide appropriate cancer surveillance or risk-reduction options. 1
Reassess PARP inhibitor eligibility for patients with ovarian cancer if the variant is confirmed pathogenic. 2
If Downgraded to Benign/Likely Benign
Revert to family history-based risk assessment and discontinue any VUS-related monitoring or anxiety. 1
Inform tested family members that the variant is not clinically significant and does not require further action. 1
Special Considerations for Ovarian Cancer Patients
Treatment Implications
For newly diagnosed ovarian cancer patients, germline BRCA testing (including VUS identification) should be performed to guide PARP inhibitor eligibility, but VUS alone does not qualify for targeted therapy. 2
Consider somatic tumor testing in addition to germline testing, as somatic BRCA mutations may be present even with germline VUS, potentially qualifying patients for PARP inhibitors. 2
Mainstreamed Genetic Testing Context
In mainstreamed testing programs (where oncologists order testing directly), VUS rates of 14-18% are common, and only 22% of VUS cases receive appropriate genetics referral. 2
Institutional protocols should mandate genetics consultation for all VUS results to prevent the documented pattern of inappropriate cascade testing and surgical decisions. 1, 2