Real-world effects of using gnomAD 4.1.0 and AllofUs population reference datasets on reporting of variants of uncertain significance.

Purpose: Clinical testing of rare genetic variants relies on population genomic datasets as a source of evidence. New datasets from the Genome Aggregation Database (gnomAD) and AllofUs Research Program are many-fold larger than prior datasets, and the latter includes highly detailed phenotype data. The effect of these datasets on variant classification and reporting for highly-penetrant pediatric-onset disease is not well characterized, but one likely effect is to reduce reporting of variants of uncertain significance (VUS).

Methods: We retrospectively identified VUS previously reported by our CAP/CLIA certified laboratory and evaluated whether they are still reportable provided new reference datasets.

Results: By examining allele counts in new datasets, we identified 24 variants that are likely no longer reportable. Additionally, the AllofUs phenotype data suggest an additional 10 VUS are no longer reportable. Overall, we find that nearly one fifth of VUS (34/173, 19.6%) are no longer reportable.

Conclusion: We conclude that the use of these new datasets is likely to reduce reported VUS for highly-penetrant pediatric-onset disease. This may be further augmented through updated gene-specific thresholds and improved accessibility of AllofUs phenotype data.