Reclassification Is All You Missed: Surfacing Variant Reinterpretation Need in Online Health Communities at Population Scale

Kamalakkannan Ravi, Mengshu Nie, Annapurna Poduri, Cong Liu

Genetic variants are routinely reclassified in ClinVar after a patient is tested, sometimes from uncertain to pathogenic, yet patient recontact is inconsistent, with no clear duty and responsibility diffused among labs, providers, and patients. Many affected people discuss their results in public online health communities that clinical recontact often does not reach. We built PRISM, an agentic large-language-model pipeline that screens these posts, checks whether the variant was later reclassified, and drafts a disclaimer-bearing outreach message, in a no-contact dry run. Across 3.9 million posts from 32 communities, agent-predicted reinterpretation-relevant discussion is rare (0.288%) but concentrated in specialist genetics communities (6.30% versus 0.10% in general medical-advice communities) and growing fivefold since 2014; PRISM surfaces 123 candidate classification differences, 5 of them from an uncertain submission to pathogenic or likely pathogenic. On a held-out set of 30 real-post drafts, a clinician judged 27 factually grounded and 15 fit to send: factual accuracy is necessary but not sufficient for clinically acceptable outreach. PRISM contributes a population-scale…