ELSIcon2024: From liminality to liberation: FACTS as a case study for addressing VUSs and prioritizing equity in genomic medicine

ELSIcon2024 • Paper • June 10, 2024 

Authors:

Speaker: Jennifer K. Wagner, JD PhD (she/her/hers) – Pennsylvania State University

Scholars have long recognized challenges accompanying variants of uncertain significance (VUSs), with much discussion regarding whether and how to return such results to individuals and descriptions of individuals with VUSs as “patients in waiting” stuck in a liminal state unless and until variant reclassification occurs. Liminality—a state “betwixt and between”–for individuals with VUSs involves confusion, ambiguity, frustration, and missed opportunities for optimal care. Efforts to improve diversity in genetic/omic research are important but not a panacea. VUSs are more likely to be found within historically marginalized and excluded (non-White/European) groups, yet the evidence base and processes for variant interpretation and classification remain biased. It becomes apparent that simply expanding access to DNA testing or sequencing could inadvertently sentence individuals to a lengthy liminal VUS fate, amplifying burdens of genetics/omics. In the NCI-funded Feasibility and Assessment of a Cascade Traceback Screening (FACTS) multi-site study of an ovarian cancer genetic testing program, VUS rates were highest (36%) at the most racially and ethnically diverse site. Drawing from our experiences with FACTS and existing ELSI literature, we review VUS (re)classification anew with an attention to centering equity given human experiences of participants receiving VUS results. We highlight where data and health disparities are perpetuated, such as clinical uses of racialized population descriptors (unaddressed by the 2023 NASEM Report) and opaque variant (re)classification processes (e.g., lab business decisions prone to majoritarian/quantification pressures). We hope to initiate a conversation to guide future genomic research and medicine related to VUSs and advance health equity.

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