Supplementary file 2_Yield of actionable variants from high-risk cancer gene panel testing in guideline-eligible and ineligible individuals.docx

Positivity rates were evaluated and compared according to testing guideline eligibility and cancer site-specific recommended gene sets.</p>Results<p>In a multi-cancer panel of 29 clinically actionable genes, pathogenic or likely pathogenic variants were identified in 6.5% of individuals meeting hereditary testing criteria and 4.8% of those not meeting criteria. Overall, 22% of individuals with positive findings would have been missed had guideline-informed testing criteria been used, suggesting substantial missed diagnostic and therapeutic opportunities.

Gene-level analyses revealed higher positivity rates for BRCA2 (met: 1.2%, not met: 0.6%), BRCA1 (met: 1.0%, not met: 0.3%), and ATM (met: 0.7%, not met: 0.53%) among individuals meeting only hereditary breast and ovarian cancer criteria, and for MSH2 (met: 0.9%, not met: 0.05%), and MLH1 (met: 0.6%, not met: 0.04%), and PMS2 (met: 0.8%, not met: 0.36%) among those meeting only Lynch syndrome criteria.</p>Discussion<p>These findings indicate that strict testing criteria may miss 22% of individuals with an actionable hereditary cancer gene variant.

The use of comprehensive multi-cancer panels, alongside broader eligibility criteria, can identify individuals with hereditary cancer syndromes and improve opportunities for targeted screening, clinical management, and cascade testing for relatives.</p>