Tracking uncertainty in germline genetic testing for hereditary cancer syndromes: Sources, attributes, and resolution of variants of uncertain significance in over 1 million individuals.

• DOI: 10.1200/jco.2024.42.16_suppl.10513
• Publication Date: 2024-06-03T19:53:13Z
• Authors: Brian Reys; Britt Johnson; Elaine Chen; Yuya Kobayashi; Flavia Facio; Yi-Lee E Ting; Sarah M. Nielsen ...; Ed Esplin; Kathryn E. Hatchell; Sienna E Aguillar; Karen E Ouyang; W. Michael Korn; Swaroop E Aradhya; Sara Pirzadeh-Miller
• Keywords: Hereditary Cancer

10513 Background: Genetic testing for hereditary cancer syndromes has diagnostic, prognostic and therapeutic implications; however, variant(s) of uncertain significance (VUS) are not clinically actionable. As such, VUS a challenge to the entire medical community. Additionally, individuals from underrepresented race, ethnicity, ancestry (REA) groups disproportionately impacted by VUS. This study reports on prevalence in patients referred genetic results reclassification. Methods: Patients were diagnostic multigene panel September 2014 2022. Variants classified as benign (B), likely (LB), VUS, pathogenic (LP), or (P) using Sherloc, validated system based guidelines ACMG/AMP. Both number unique (uVUS) times they observed (oVUS) counted. All-time uVUS separated being reclassified non-reclassified, relative contribution evidence types used reclassification was analyzed. Results: During this 8-year period, 1,122,444 unrelated tested with mean 53 genes per individual. Results showed 0.45 oVUS individual; 30.6% without P/LP variant had at least 1 oVUS. The rate normalized highest French Canadian lowest Ashkenazi Jewish individuals, sequenced observe one 39.8 59.4, respectively. White lower 31.4% than Sephardic (53.8%), Asian (48.3%), Black (40.5%), Hispanic (37.6%), additional REA groups. In total, 7,542 (7.3%) 103,767 reclassified, affecting 88,877 (7.9%); 5,864 (77.8%) downgraded B/LB, 1,678 (22.2%) upgraded LP/P. Evidence clinical observation contributed most upgrading (16.0-fold compared non-reclassified uVUS), while experimental studies downgrading (23.9-fold). Conclusions: Experimental impactful reclassifications. highlights partnership among researchers, clinicians, laboratories resolve Further representation diverse genomic databases is needed address disparities rates, research into methods that could expedite resolution so can make more informed decisions.