608 - How Variants of Uncertain Significance Impact Clinical Care

Publication Number: 4595.608

Shiv Ayappa, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Steven Joffe, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States; Anne-Marie Laberge, CHU Sainte-Justine, Montreal, PQ, Canada; Russell Nye, Childrens Hospital of Philadelphia, Philadelphia, PA, United States; Molly Hess, Childrens Hospital of Philadelphia, Philadelphia, PA, United States; Katharine P. Callahan, Children's Hospital of Philadelphia, Haddonfield, NJ, United States

Background: Variants of Uncertain Significance (VUS) are genetic findings with unclear implications for health. Despite guidance from the American College of Medical Genetics warning against the application of VUS to clinical decision making, how clinicians and patients actually use VUS remains unclear. Mainstreaming of genetic testing, particularly in pediatrics, warrants a comprehensive assessment of VUS' impact.

Objective: To assess the extent to which VUS impact quantitative healthcare outcomes.

Design/Methods: We searched PubMed, Embase, Scopus and Cochrane for studies reporting VUS impact on quantitative healthcare outcomes. We limited our review to articles published in English prior to October 2024. We wrote narrative summaries of VUS' impact on each study's outcomes. Where possible, we extracted quantitative data on the effects of receiving VUS for grouped analysis. We calculated relative risks to compare the impact of VUS to that of pathogenic or benign genetic results.

Results: We included 45 articles in our overall review and 20 in our quantitative analysis (Fig. 1). The impact of VUS on clinical care was highly variable (Fig. 2); clustering into 3 patterns, where VUS were treated similarly to 1) benign; 2) "weak positives" or 3) pathogenic results (Fig. 3). A majority (55%, 11/20) of studies fit either pattern 2 or 3.VUS impacted at least one outcome for a majority (67%, 30/45) of studies. All studies in a pediatric (n=7) or prenatal (n=3) context reported an impact of VUS while nearly half in cancer-based fields (46%, 15/32) found no impact of VUS. VUS were more likely to impact care if studies were prospective, reported clinician- versus patient-centered outcomes, and reported screening versus definitive care outcomes. VUS were less likely to impact care in larger studies and those that reported actual rather than hypothetical patient care. Limitations of our analysis include: (1) study heterogeneity precluded true meta-analysis and (2) clinicians may have additional information informing VUS interpretation that is not captured in manuscripts.

Conclusion(s): The results of our systematic review convincingly demonstrate that VUS do frequently, though inconsistently, impact clinical care. VUS are treated as benign, pathogenic, or something in between. Given the realities of human psychology, expecting patients and clinicians to receive but ignore information may be unreasonable. We must shift our attention to identifying the downstream impact-both benefits and harms-of disclosing VUS. Lessons from VUS warrant careful consideration of the implications of uncertain results in all realms of medicine.

PRISMA flow diagram
This flowchart documents the search and screening process for studies included in systematic review

Relative risk associated with pathogenic and VUS results
Filled markers/solid lines indicate studies of real clinical practice, while open markers/dashed lines indicate studies using hypothetical clinical cases. Relative risks associated with benign genetic results are the baseline (RR = 1). Relative risk is set at a maximum of 10 for purposes of display.

Change in relative risk for VUS compared to pathogenic results
For this analysis, if papers reported multiple primary outcomes, we selected the one showing the greatest impact of VUS to display. Relative risk is set at a maximum of 5 for purposes of display.