2025 Theses Master's

Comparison of Reclassification Rates of Variants of Uncertain Significance by Patient-Reported Ancestry in a General Genetics Cohort

Keth, Alexander; Rekab, Aisha; Telegrafi, Aida; Ahimaz, Priyanka Rebecca

Introduction: Variants of uncertain significance (VUS) from genetic testing represent a challenge in clinical practice due to insufficient evidence to determine pathogenicity and can complicate clinical decision-making. Reclassification of VUS results is critical for improving diagnostic accuracy and reducing patient uncertainty. Due to underrepresentation in genomic reference databases, individuals of non-European backgrounds are more likely to receive VUS results than those with European ancestry. This disparity suggests that non-European patients may experience prolonged diagnostic uncertainty. Although this inequity is well documented, it remains unclear whether similar disparities extend to VUS reanalysis and reclassification processes. Emerging research suggests potential differences in VUS reclassification rates between populations, however, most studies do not report statistical significance, with limited evidence across clinical context.

Study Aim: Evaluate differences in VUS reclassification proportion and the time to reclassification of VUS results across different patient-reported racial, ethnic, and ancestry (REA) groups in a general genetics clinic.

Methods: A retrospective chart review was conducted of 973 pediatric and adult patients at a New York City general genetics clinic who underwent genetic testing through Invitae or GeneDx between 2016 and 2023 resulting in at least one VUS. Data extracted included patient-reported REA, test type (panel vs. exome/genome), reanalysis status and outcome, time from initial testing to reanalysis, and type of reclassification (upgrade vs. downgrade). Patient-reported REA data were categorized based on the National Institute of Health classifications. Chi-square tests assessed differences in reclassification proportions, and two-sample T-tests and one-way ANOVA tests were used to evaluate differences in time to reanalysis between populations. Statistical significance was set at <0.05.

Results: Of the 973 patients, 238 (24.5%) underwent reanalysis, and 193 (19.85%) had at least one VUS reclassified to likely benign/benign (148; 76.7%) or likely pathogenic/pathogenic (45; 23.3%). Of the 238 reanalyzed, 136 (57.1%) were lab-initiated and 71 (29.8%) were provider-initiated reanalysis. The average time to reanalysis was 2.74 years (SD=1.94). Reclassification rates did not differ significantly between European and non-European patients (p=0.92), or between different non-European subgroups (p=0.72). However, European patients with Ashkenazi Jewish (AJ) ancestry had significantly higher reclassification rates compared to those without AJ ancestry (29.5% vs 17%; p=0.003), with relative risk analysis showing a 73% higher likelihood of reclassification. No significant differences were noted in time to reclassification between any of the REA groups.

Conclusions: In this general genetics cohort, VUS reclassification proportion and time to reclassification were largely comparable across REA groups, suggesting that although higher rates of VUS results are noted among underrepresented REA populations, this disparity may not extend to reclassification outcomes due to robust efforts to initiate reanalysis by labs and clinical providers. The higher reclassification proportion among individuals with AJ ancestry represents a novel finding that may be explained by stronger representation in genomic databases, thereby facilitating more efficient reclassification of VUS results; alternatively, this could reflect inherent sampling bias. Nonetheless, the data underscores the importance of periodic reanalysis efforts by labs and clinical providers as well as increasing diversity in genomic research to improve variant interpretation and promote equity in genetic care.

Keywords: variant of uncertain significance; reclassification; genetic testing; race, ethnicity, and ancestry, patient-reported; general genetics clinic