Clinical implications of conflicting variant interpretations in the cancer genetics clinic.

Purpose: The aim of this study was to describe the clinical impact of commercial laboratories issuing conflicting classifications of genetic variants.
Methods: Results from 2000 patients undergoing a multigene hereditary cancer panel by a single laboratory were analyzed. Clinically significant discrepancies between the laboratory-provided test reports and other major commercial laboratories were identified, including differences between pathogenic/likely pathogenic and variant of uncertain significance (VUS) classifications, via review of ClinVar archives. For patients carrying a VUS, clinical documentation was assessed for evidence of provider awareness of the conflict.
Results: Fifty of 975 (5.1%) patients with non-negative results carried a variant with a clinically significant conflict, 19 with a pathogenic/likely pathogenic variant reported in APC or MUTYH, and 31 with a VUS reported in CDKN2A, CHEK2, MLH1, MSH2, MUTYH, RAD51C, or TP53. Only 10 of 28 (36%) patients with a VUS with a clinically significant conflict had a documented discussion by a provider about the conflict. Discrepant counseling strategies were used for different patients with the same variant. Among patients with a CDKN2A variant or a monoallelic MUTYH variant, providers were significantly more likely to make recommendations based on the laboratory-reported classification.
Conclusion: Our findings highlight the frequency of variant interpretation discrepancies and importance of clinician awareness. Guidance is needed on managing patients with discrepant variants to support accurate risk assessment.
Competing Interests: Conflict of Interest Gregory E. Idos reports research funding from Myriad Genetics (Inst). Jason A. Zell serves in a consulting role for Tempus. Charité N. Ricker reports research funding from Myriad Genetics (Inst). Kevin J. McDonnell has served in a consulting or advisory role for Brogent International and reports research funding from Myriad Genetics. Uri Ladabaum serves as an advisor for Universal Dx, Lean Medical, Kohler Ventures, Vivante, and a consultant for Freenome, Guardant, Medtronic, Neptune Medical, Medial EarlySign. Stephen B. Gruber reports that he is co-founder with equity with Brogent International. Giovanni Parimigiani reports that he holds equity as a co-founder in Phaeno Biotechnologies, is on the SAB of Realm Idx (which owns Ambry Genetics) and currently consults for Delphi Diagnostics and (pro bono) for Martingale Labs. He also co-leads the BayesMendel laboratory, which licenses the BayesMendel package which include several ML tools for the computation of carrier probability of cancer susceptibility genes and future cancer risk. He does not derive any personal income from these licenses. Danielle Braun co-leads the BayesMendel lab, which develops and maintains the BayesMendel software package. This includes a variety of risk assessment tools, including BRCAPRO, PancPRO, MelaPRO, MMRpro and is licensed for commercial use. All other authors declare no conflicts of interest.
(Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)