Introduction:
Variants of uncertain significance (VUS) are frequently encountered during clinical genetic testing and can result in uncertain clinical recommendations. Although our understanding of the rate of VUS return has been well documented by clinical labs, the overall clinical burden of VUS across a broader adult clinical context remains largely unresolved. To explore the clinical and patient burden of VUS, we developed the Brotman Baty Institute Clinical Variant Database (BBI-CVD), which is an Electronic Health Record (EHR)-linked database of clinical germline genetic variant information from patients with rare genetic disorders seen at two tertiary academic medical centers, the University of Washington Adult Genetics clinic as well as the Fred Hutchinson Cancer Genetics clinic. 

Methods:
We retrospectively reviewed EHRs and genetic testing reports from 5,158 patients seen across diverse adult genetics practices at these institutions from 2015 to 2024. We also generated the BBI-CVD browser for disseminating this information. For our cohort, we assessed the burden of VUS as well as the diagnostic rate of genetic testing reports across 3 categories: the primary indication for genetic testing, multigene panel size, and self-identified race. VUS burden was assessed using two metrics: the ratio of VUS variants reported per each Pathogenic (P) or Likely Pathogenic variant (LP), and the number of VUS reported per test. The diagnostic rate was assessed by assigning values to reported variants where VUS were classified as “non-diagnostic”, and P/LP variants were manually reviewed and classified as “diagnostic” or “carrier/non-diagnostic” based on the interpretation documented in the EHR by the patient’s genetics provider. Additionally, we assessed the concordance of the variant classifications in the BBI-CVD with the most recent classifications for that variant in ClinVar.

Results:
In the BBI-CVD there were a total of 5694 variants reported from sequence-based testing, of which 50.8% (2897) were classified as VUS. We found that the number of reported VUS relative to Pathogenic or Likely Pathogenic variants can vary by over 14-fold depending on the primary indication for genetic testing, 6-fold depending on multigene panel size, and 3-fold depending on self-reported race. Similarly, we found that the proportion of patients who received a diagnostic genetic test result can vary by 3-fold depending on primary indication for genetic testing, 2-fold depending on multigene panel size, and 2-fold depending on self-identified race. We also found that 3.17% (181 variants) of the  variant classifications in our EHR were discordant with the most recent consensus classifications for that variant in ClinVar. 65% (119 variants) of these discordant variants were classified as VUS in our EHR but have subsequently been updated to either Benign/Likely benign, or Pathogenic/Likely Pathogenic in ClinVar, indicating that 4.16% of VUS interpretations  that patients are currently being managed by are outdated based on current ClinVar variant interpretations.

Conclusion:
Using the BBI-CVD, we were able to identify the burden of VUS on clinicians and patients in adult medical genetics practices, and further disentangle the various factors contributing to the burden of VUS. Additionally, we demonstrated that the burden of VUS is not equally shouldered by all patients. These findings add the context of medical genetics clinics to published studies examining the burden of VUS from clinical labs to better elucidate the impacts of VUS on different patient populations. Through our comparison of the variant classification in our EHR to the most recent classifications in ClinVar, we also highlight a deficiency in existing systems for returning variant reinterpretations to patients and providers.