Precision Health Genetic Screening: Protocol and results categories for a clinical population genetic screening...

As population genetic screening (PGS) gains traction with declining genetic sequencing costs and increased interest in personal health genetics, multiple diverse programs are being implemented throughout the nation. We introduce a clinical program embedded in a large healthcare system.

The UNC Precision Health Genetic Screen (PHGS) is a clinical PGS program analyzing three CDC Tier 1 genetic conditions: Hereditary Breast and Ovarian Cancer syndrome (HBOC), Lynch syndrome (LS), and Familial Hypercholesterolemia (FH).

From the summer of 2021 through March 2026, the UNC PHGS returned 348 test results: 331 negatives and 16 positives (8 HBOC, 4 LS, 4 FH). One negative result was later reclassified from an unreported Variant of Uncertain Significance (VUS) to Likely Pathogenic (increasing to 17 positive results and FH to 5). The PHGS team developed internal results categories to contextualize results with reported personal and family history; these 6 categories help indicate how reassuring negative results could be to the individual. Negative results were "aligned with history provided" (n=208), "unaligned with family history" (n=113, later 112), or "unaligned with personal history" (n=11). Positive results were "unaligned with history provided" (n=7), "aligned with family history" (n=9, later 10), or "aligned with personal history" (n=0).

As PGS programs monitor their clinical outcomes, it will be important to categorize both positive and negative results in terms that reflect the underlying chance of a monogenic condition, to identify potential participants for whom clinical diagnostic testing would have been warranted, and reduce the potential for false reassurance among those with negative screening results.