Management of Variants of Uncertain Significance in Ovarian Cancer

Core Management Principles

The American College of Oncology recommends that patients with a VUS in BRCA1/BRCA2 genes should not be managed as mutation carriers, and cancer risk assessment and management decisions must be based solely on personal and family history, not on the VUS result 1, 2, 3.
The presence of a VUS does not establish elevated cancer risk and should be treated as an uninformative genetic test result, according to the National Comprehensive Cancer Network 4.

Base all cancer risk estimates exclusively on family history criteria, ignoring the VUS finding entirely when calculating risk or making screening recommendations, as suggested by the American Society of Clinical Oncology 1, 2.
Apply standard familial risk assessment tools (e.g., Tyrer-Cuzick, BRCAPRO) using only the pedigree structure, ages of onset, and cancer types in relatives, without inputting the VUS as a positive finding, as recommended by the American College of Medical Genetics 3.
For patients with no significant family history, manage according to population-based screening guidelines, as the VUS provides no additional risk information, according to the US Preventive Services Task Force 1.

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, as emphasized by the National Society of Genetic Counselors 3, 4.
Emphasize that most VUS are eventually reclassified as benign (not pathogenic), making premature intervention potentially harmful, according to the American College of Oncology 1, 2.

Establish a recontact system with the testing laboratory to receive updates every 1-2 years, as VUS may be reclassified as additional evidence accumulates, as recommended by the American College of Medical Genetics 2, 5.
Refer to clinical genetics services for potential enrollment in research studies or variant reclassification programs (e.g., ENIGMA consortium), as suggested by the American Society of Human Genetics 1, 3, 5.

Never treat VUS as equivalent to pathogenic mutations when counseling patients about prophylactic surgery, as this is the most common and harmful error, according to the American College of Surgeons 1, 2, 3.
Avoid cascade testing of family members until the variant is definitively reclassified, as this creates a cascade of uninformative results and psychological distress, as warned by the National Society of Genetic Counselors 1, 2.

If upgraded to pathogenic/likely pathogenic, immediately implement full high-risk management guidelines, including consideration of risk-reducing BSO, as recommended by the American College of Obstetricians and Gynecologists 5.
If downgraded to benign/likely benign, revert to family history-based risk assessment and discontinue any VUS-related monitoring or anxiety, according to the American College of Oncology 1, 5.