What is the management approach for a patient with a Variant of Unknown Significance (VOUS) result in genetic testing, particularly in the context of a genetic disorder or cancer susceptibility?

Management of Variants of Uncertain Significance (VOUS/VUS) in Genetic Testing

A VUS result is not clinically actionable and must never guide medical management—patients should be managed based solely on their personal and family history, exactly as if the genetic test had never been performed. 1, 2

Core Management Principle

VUS results should be treated as uninformative genetic tests that provide zero additional risk information. 1, 2 The most critical error in VUS management is treating these variants as pathogenic mutations, which leads to unnecessary interventions including prophylactic surgeries that cause real clinical harm. 1, 3

• VUS occur in 5-20% of BRCA1/2 tests depending on ethnic background, with rates up to 20% in underrepresented populations and as low as 5% in well-characterized European ancestry populations. 1
• Most VUS are eventually reclassified as benign (not pathogenic), with 97% of reclassified VUS being downgraded to benign variants. 4
• VUS identification is not a diagnosis and confers no established cancer risk or disease susceptibility. 1

Clinical Management Algorithm

Risk Assessment Without the VUS

Base all cancer risk estimates exclusively on family history criteria, completely ignoring the VUS finding when calculating risk or making screening recommendations. 1, 2

• Apply standard familial risk assessment tools (Tyrer-Cuzick, BRCAPRO, or similar models) using only the pedigree structure, ages of onset, and cancer types in relatives—do not input the VUS as a positive finding. 2
• For patients with no significant family history, manage according to population-based screening guidelines since the VUS provides no additional risk information. 2
• For patients with strong family history, manage according to the family history risk category regardless of VUS status. 1

Disease-Specific Contexts

In hypertrophic cardiomyopathy (HCM), VUS in sarcomere genes requires continued clinical surveillance based on phenotype, not genotype. 1

• Family members where genetic testing is negative or shows only VUS require clinical screening at regular intervals based on family history alone. 1
• VUS can be investigated further through cosegregation analysis in family members, parental DNA testing to determine if the VUS is de novo, or functional studies—but these are research activities, not clinical management tools. 1

In BRCA testing for hereditary breast and ovarian cancer, VUS results demand explicit counseling that no risk-reducing interventions are indicated. 1

• Patients with VUS and no significant family history should follow population screening guidelines. 1, 2
• Patients with VUS and strong family history should be referred to genetic specialist services for family history-based risk management. 1

Genetic Counseling Requirements

Pretest Counseling

Explicitly explain during pretest counseling that VUS results are possible and that such results cannot guide medical management. 1, 2

• Inform patients that in those with low a priori probability of finding a pathogenic variant, the most likely outcome is no pathogenic variant found, the second most likely is a VUS, and the least likely is a pathogenic variant. 1
• Discuss that VUS results create uncertainty and may cause psychological distress without providing actionable information. 5, 6
• Emphasize that most VUS are eventually reclassified as benign, making premature intervention potentially harmful. 2, 4

Posttest Counseling for VUS Results

Patients with VUS should receive individualized posttest genetic counseling emphasizing that the result is uninformative and should be offered referral to a provider experienced in clinical cancer genetics. 1

• Clearly explain that VUS means insufficient evidence exists to classify the variant as either pathogenic or benign. 1
• Patients with VUS reported higher genetic test-specific concerns than those with negative results but lower concerns than those with positive results on validated scales. 5
• Address both emotional and intellectual responses to VUS results, as patients often interpret VUS within the context of their personal and family history despite understanding the lack of clinical significance. 6

Cascade Testing Prohibition

Never perform cascade testing of family members for a VUS—this creates a cascade of uninformative results and unnecessary psychological distress. 1, 2

• VUS cannot be used for predictive testing in family members until definitively reclassified as pathogenic or likely pathogenic. 1, 7
• If affected family members exist with confirmed disease, consider testing them first to determine if the VUS segregates with disease as part of variant reclassification efforts, not clinical management. 4

Variant Reclassification Strategy

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, 2, 4

• Laboratories should implement standard operating procedures to review variant classification each time new evidence emerges. 1
• A clearly agreed process must exist for reporting updated classifications by laboratories and recontacting patients by clinicians if a VUS becomes reclassified. 1
• The American College of Medical Genetics and Genomics emphasizes that recontacting is a shared responsibility of the healthcare provider, clinical geneticist, clinical laboratory, patient, and family. 1

Research Participation

Refer patients to clinical genetics services for potential enrollment in research studies or variant reclassification programs such as the ENIGMA consortium. 1, 2

• Patients can submit medical information, genetic test reports, and tumor pathology reports to variant-specific research registries. 1
• Collaboration across centers with the same VUS allows segregation analysis and pooling of evidence for reclassification. 1
• Multiple lines of evidence including segregation analysis, functional studies, and multifactorial likelihood models are required to reclassify many VUS. 1

Management When VUS Is Reclassified

If upgraded to pathogenic/likely pathogenic, immediately implement full high-risk management guidelines appropriate for that specific gene and condition. 2

• For BRCA1/2, this includes consideration of risk-reducing bilateral salpingo-oophorectomy and mastectomy based on age and reproductive plans. 2
• For HCM sarcomere genes, this triggers cascade testing of first-degree relatives for the now-confirmed pathogenic variant. 1

If downgraded to benign/likely benign, revert to family history-based risk assessment and discontinue any VUS-related monitoring or anxiety. 2

• Clearly document the reclassification in the medical record to prevent future confusion. 4
• Inform family members who were aware of the VUS that it has been resolved as benign. 1

Critical Pitfalls to Avoid

Never treat VUS as equivalent to pathogenic mutations when counseling patients about prophylactic surgery—this is the most common and harmful error. 1, 2, 3

• Case reports document unnecessary bilateral mastectomies and oophorectomies performed based on VUS misinterpretation. 3
• Misinterpretation of VUS can lead to real clinical harms for both patients and families, including inappropriate interventions and psychological distress. 1

Avoid implementing disease-specific interventions in asymptomatic VUS carriers. 4

• Do not restrict exercise or implement dietary modifications for metabolic disease VUS without biochemical confirmation of disease. 4
• Do not initiate enzyme replacement therapy or aggressive clinical management based on VUS alone. 1

Document clearly in the medical record that clinical decisions should not be based on the VUS to prevent mismanagement by other providers. 4

• Variability in genetic test report terminology across laboratories creates confusion—some use "uncertain variant," "VUS," "VOUS," or narrative descriptions. 1
• Laboratories with limited gene-specific experience may provide more categoric conclusions than evidence supports. 1

System-Level Recommendations

Improve genetics literacy of medical providers through structured training and integration of genomics into medical education curricula. 1

• Testing clinicians must understand possible outcomes before ordering tests and be able to estimate the probability of finding a pathogenic variant given family history. 1
• Consultation with a provider experienced in clinical cancer genetics is recommended if the ordering provider is uncertain about appropriate gene panels or interpretation of results. 1

Establish clear referral guidelines to specialist clinical genetics services for patients with VUS, pathogenic variants, or strong family history without detectable genetic cause. 1

• A close working relationship between genetic diagnostic laboratories, genetic specialists, and disease specialists delivers optimal integrated care. 1
• Multidisciplinary team meetings between oncologists and geneticists facilitate appropriate VUS management. 1