What are the implications and management options for a Variant of Unknown Significance (VUS) found on Electronystagmography (ENG) results?

Management of Variant of Unknown Significance (VUS) in Genetic Testing

Critical Management Principle

A VUS should never be used to guide clinical management, dietary interventions, or treatment decisions—the patient must be managed based solely on their clinical phenotype and family history, not the genetic finding. 1, 2

Understanding VUS Classification

• VUS represents insufficient evidence for pathogenicity and must not direct clinical decisions, as the clinical significance cannot be inferred from sequence information alone 1
• Most VUS are eventually reclassified as benign, with 97% of reclassified VUS being downgraded to benign rather than upgraded to pathogenic 2
• VUS results occur in up to 20% of genetic tests in well-characterized populations, but may drop to 5% or less in specific ethnic groups with established founder mutations 1
• Different laboratories use inconsistent classification systems and reporting standards, leading to variability in how VUS are described and interpreted 1

Clinical Management Algorithm

Step 1: Base All Decisions on Clinical Presentation

• If the patient is symptomatic, proceed with functional testing (biochemical assays, enzymatic analysis, imaging) to establish a diagnosis independent of the genetic finding 2
• Calculate disease risk estimates based exclusively on personal and family history, completely disregarding the VUS result 1
• Continue standard clinical surveillance protocols appropriate for the patient's phenotype and family history 1

Step 2: Avoid Premature Clinical Actions

• Do not implement preventive surgeries, dietary modifications, exercise restrictions, or prophylactic interventions based on VUS results 1, 2
• Do not initiate cascade testing of family members until the variant is reclassified as pathogenic or likely pathogenic 1, 2
• Misinterpretation of VUS can lead to real clinical harms, including unnecessary radical medical decisions 1

Step 3: Pursue Variant Reclassification

• Refer the patient to research studies and variant reclassification programs to help resolve the variant's significance 2
• If affected family members exist with confirmed disease, test them first to determine if the VUS segregates with disease (cosegregation analysis) 1
• Additional evidence for reclassification may include: functional assays, RNA analyses, tumor pathology correlation, and multifactorial likelihood models combining multiple lines of evidence 1

Step 4: Establish Systematic Follow-Up

• Establish a recontact system with the genetics laboratory every 1-2 years for variant reclassification updates 2
• Laboratories should implement policies to reevaluate variants based on new information, though they currently lack standardized mechanisms for patient recontact 1
• Document clearly in the medical record that clinical decisions should not be based on the VUS to prevent mismanagement by other providers 2

Genetic Counseling Requirements

• Provide pre-test genetic counseling to ensure patients understand that VUS is a possible outcome with no clinical actionability 1
• Provide post-test genetic counseling emphasizing that VUS should not be used for predictive testing of family members 1, 2
• Explain that variant interpretation may change over time, and recontacting is a shared responsibility of the healthcare provider, laboratory, patient, and family 1
• Address the psychological impact, as patients frequently misinterpret VUS as pathogenic, leading to overestimation of cancer risks and adverse psychological outcomes 1

Critical Pitfalls to Avoid

• Treating VUS as pathogenic variants: Many clinicians and patients assume any reported variant must be disease-causing unless uncertainty is clearly communicated 1
• Cascade testing based on VUS: Testing relatives cannot provide useful segregation information and wastes resources when the proband's variant significance is unknown 1
• Implementing preventive interventions: The same large number of patients with VUS decide to have preventive surgery as those with pathogenic variants, representing inappropriate management 1
• Ignoring laboratory variability: Laboratories with limited gene-specific experience may issue reports with more categorical conclusions than evidence supports 1
• Assuming rarity equals pathogenicity: Clinicians and patients often incorrectly reason that a rare variant found in a patient with disease cannot be coincidental 1

Special Considerations for Specific Contexts

• Direct-to-consumer or broad panel testing increases VUS detection rates, particularly as sequencing extends to untranslated and deeper intronic regions 1
• For intermediate penetrance genes, cosegregation analyses (helpful for high-penetrance genes like BRCA1/2) are not recommended for variant classification 1
• Variant interpretation requires integration of multiple independent lines of evidence including evolutionary conservation, functional assays, tumor pathology, and family segregation data 1

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Note: The question appears to reference "ENG VUS" which could be misinterpreted as Electronystagmography results. However, ENG is a vestibular function test that measures eye movements and does not generate genetic variants 3, 4, 5. This response addresses VUS in genetic testing, which is the clinically relevant interpretation of "VUS" in medical practice.