Residency · Residency · Medical Genetics Genomics
Uncertain Results in Genomic Medicine: Counseling for VUS
Introduction
Variants of uncertain significance (VUS) are among the most challenging results to communicate and manage in genomic medicine. As sequencing expands into broader clinical practice, VUS constitute the most common reportable finding, often outnumbering pathogenic and likely pathogenic variants. Effective counseling for VUS requires understanding classification systems, reclassification processes, and strategies for managing clinical uncertainty.
Understanding VUS in the ACMG Framework
The Five-Tier Classification System
The ACMG/AMP framework classifies variants into five tiers: Pathogenic (sufficient evidence to establish causality with disease), Likely Pathogenic (greater than 90% probability of being disease-causing), Variant of Uncertain Significance (insufficient evidence to classify as pathogenic or benign), Likely Benign (greater than 90% probability of being benign), and Benign (sufficient evidence to establish the variant is not disease-causing).
Why VUS Are So Common
The sheer number of variants identified by broad sequencing (exome: approximately 80,000-100,000; genome: approximately 4-5 million) ensures many will be poorly characterized. Limited data on rare variants, particularly in underrepresented populations, prevents classification. Novel missense variants with amino acid changes of uncertain functional impact are frequently encountered. Expanding gene panels include genes with less well-characterized variant spectra. The ongoing nature of scientific knowledge means today's VUS may be classifiable with future data.
VUS Rates by Context
Multigene hereditary cancer panels produce VUS rates of 20-40% per patient depending on panel size. Higher VUS rates (up to 2-3x) occur in individuals of non-European ancestry. VUS rates increase with panel size, as more genes tested means more VUS identified. Single-gene testing typically produces VUS rates of 5-15%.
Clinical Management of VUS
What a VUS Does NOT Mean
A VUS is not a diagnosis and should not drive clinical management changes. It does not mean "probably pathogenic" despite the word "uncertain." The majority of VUS are ultimately reclassified as benign or likely benign over time, with estimates suggesting more than 90% of reclassified VUS are downgraded.
Management Principles
Clinical management should not change based on a VUS alone but should be driven by personal and family history. If the phenotype is strongly suggestive, the VUS may be considered in context but should not serve as confirmatory evidence of the clinical diagnosis. Periodic re-evaluation is recommended as VUS may be reclassified when new evidence emerges; laboratories should be contacted for updates every 1-2 years. Cascade testing should not be ordered for a VUS in family members as a clinical test, though segregation studies for research purposes may be appropriate with informed consent.
Segregation Analysis
If a VUS is identified in a patient with a suggestive phenotype, testing affected and unaffected family members can provide evidence for or against pathogenicity. Co-segregation of the VUS with the phenotype in multiple affected individuals supports pathogenicity (PP1 criterion). Absence of the VUS in affected relatives argues against pathogenicity. This constitutes research-level investigation and requires appropriate consent and context.
Counseling Strategies for VUS
Pre-Test Counseling
Patients should be prepared for the likelihood of a VUS result before testing. The range of possible outcomes including the high probability of uncertain results with broad panels should be discussed. Appropriate expectations should be set: "The most common result is a variant that we don't have enough information about yet." Implications for family members should be discussed proactively.
Delivering VUS Results
Clear, plain language should be used: "We found a change in your DNA that we don't have enough information about to know if it's causing a problem or not." Emphasis should be placed on the VUS not being a positive result or a diagnosis. The dynamic nature of classification should be explained: "As we learn more, this result may change." VUS should not be labeled as "mutations," which implies pathogenicity to patients. Written documentation with the laboratory's contact information for future reclassification inquiries should be provided.
Addressing Patient Anxiety
The difficulty of uncertainty should be acknowledged, and the patient's emotional response validated. Many patients experience VUS results similarly to positive results in terms of anxiety and distress. Reassurance that clinical care will be guided by history, not the VUS, should be provided. Patients who may need additional psychological support should be identified. Follow-up should be scheduled to address emerging questions and reassess over time.
VUS Reclassification
Triggers for Reclassification
New functional data from in-vitro or in-vivo assays may demonstrate the variant's effect on protein function. Updated population frequency data from gnomAD and other databases may identify a VUS as common and likely benign. Additional clinical observations from new case reports may link the variant to a concordant phenotype. Segregation data from family studies may demonstrate co-segregation or lack thereof. ClinGen expert panel classifications provide definitive variant curation. Computational advances including improved in-silico prediction algorithms (such as AlphaMissense) contribute new evidence.
Laboratory Responsibilities
Clinical laboratories have professional obligations to periodically re-evaluate reported VUS. ACMG recommends laboratories reassess VUS when prompted by the ordering provider or when significant new evidence emerges. Some laboratories proactively contact ordering providers when a VUS is reclassified through automated reclassification alerts. Patients and providers should maintain a system for tracking VUS for future reclassification inquiries.
| VUS Aspect | Key Facts | Clinical Implication |
|---|---|---|
| Frequency | 20–40% of patients on multigene panels receive ≥1 VUS | Pre-test counseling must prepare patients for this likely outcome |
| Population disparity | 1.5–2x higher VUS rates in non-European ancestry | Greater uncertainty in underrepresented populations |
| Reclassification rate | ~5–10% of VUS reclassified per year | Periodic laboratory follow-up recommended every 1–2 years |
| Direction of reclassification | ~90% downgraded to likely benign/benign | Most VUS are ultimately not disease-causing |
| Upgrade to pathogenic/LP | ~5–10% of reclassified VUS | Small but clinically significant subset requires management change |
| Clinical management | Should NOT change based on VUS alone | Manage by personal/family history, not VUS |
| Cascade testing | NOT recommended for VUS | Segregation studies for research only (with consent) |
Reclassification Rates
The annual reclassification rate is approximately 5-10% of VUS per year. Higher reclassification rates occur for variants in well-studied genes such as BRCA1/2, MLH1, and TP53. The direction of reclassification is overwhelmingly toward benign/likely benign (approximately 90% of reclassified VUS). Reclassification to pathogenic/likely pathogenic occurs in approximately 5-10% of reclassified VUS.
Institutional Best Practices
Standardized VUS tracking systems with automated reminders for recontact should be developed. Templates for patient-facing VUS result letters in plain language improve communication. Policies for recontacting patients when clinically significant reclassifications occur should be established. Continuing education for non-genetics providers who may encounter VUS on reports reduces mismanagement. Genetic counseling should be used for VUS results whenever possible, as primary care providers often lack the training for nuanced VUS communication.
Clinical Pearls
A VUS should never drive clinical management changes; management should be based on personal and family history, not on the VUS. The vast majority of reclassified VUS are downgraded to likely benign or benign; patients should be counseled that a VUS is not equivalent to a positive result. Pre-test counseling that prepares patients for the high likelihood of VUS results reduces post-test anxiety and improves understanding. Periodic re-evaluation of VUS is essential; clinicians should have a system for tracking VUS and contacting laboratories for reclassification updates at 1-2 year intervals.
References
- Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the ACMG and AMP. Genetics in Medicine. 2015;17(5):405-424.
- Mersch J, Brown N, Pirzadeh-Miller S, et al. Prevalence of variant reclassification following hereditary cancer genetic testing. JAMA. 2018;320(12):1266-1274.
- Makhnoon S, Garrett LT, Burke W, et al. Experiences of patients seeking to participate in variant reclassification. Journal of Community Genetics. 2019;10(3):293-301.
- Murray ML, Cerrato F, Bennett RL, Jarvik GP. Follow-up of carriers of BRCA1 and BRCA2 variants of unknown significance: variant reclassification and surgical decisions. Genetics in Medicine. 2011;13(12):998-1005.