Opportunistic screening for broad range of medically relevant secondary findings: Laboratory benefits and burdens

Exome and genome sequencing enable opportunistic screening for secondary findings (SFs). We report on exome analysis for a broad range of medically relevant SFs in the setting of the Incidental Genomics randomized clinical trial (NCT03597165).

Participants had exome sequencing and were randomized to receive only primary cancer findings (control) or cancer findings and a choice of SFs (intervention).

Across 279 participants, there were 4441 unique variants in SF genes: 5.0% (221) were reportable pathogenic/likely pathogenic variants, and 81.4% (3615) were nonreportable variants of uncertain significance (VUS). Intervention arm participants had on average 2.6 (SD 1.66, range 0-9) pathogenic/likely pathogenic variants and 29.5 VUS (SD 13.2, range 2-74). SFs for monogenic disease risk were reported in 35.3% (49/139) of participants (American College of Medical Genetics and Genomics non-cancer subset in 1.4%) and carrier status in 89.3% (117/131). In the intervention arm, variant filtration was 7.7 times longer per case (95% CI 5.3 to 11.3, P < .0001), variant classification was 13.3 times longer (95% CI 10.6 to 16.5, P < .0001), and report preparation was 3.3 times longer (95% CI 2.6 to 4.1, P < .0001).

Although the yield of reportable SFs was high, this was accompanied by many nonreportable VUS and increased efforts for exome analysis.