Assessments of Somatic Variant Classification Using the Association for Molecular Pathology/American Society of Clinical Oncology/College of American Pathologists Guidelines

To assess the clinical implementation of the 2017 Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists, identify content that may result in classification inconsistencies, and evaluate implementation barriers, an Association for Mo-lecular Pathology Working Group conducted variant interpretation challenges and a guideline imple-mentation survey. A total of 134 participants participated in the variant interpretation challenges, consisting of 11 variants in four cancer cases. Results demonstrate 86% (range, 54% to 94%) of the respondents correctly classified clinically significant variants, variants of uncertain significance, and benign/likely benign variants; however, only 59% (range, 39% to 84%) of responses agreed with the working group's consensus intended responses regarding both tiers and categories of clinical significance. In the implementation survey, 71% (157/220) of respondents have implemented the 2017 guidelines for variant classification and reporting either with or without modifications. Collectively, this study demonstrates that, although they may not yet be optimized, the 2017 guideline recommendations are being adopted for standardized somatic variant clas-sification. The working group identified significant areas for future guideline improvement, including the need for a more granular and comprehensive classification system and education resources to meet the growing needs of both laboratory professionals and medical oncologists. (J Mol Diagn 2023, 25: 69-86; https://doi.org/10.1016/j.jmoldx.2022.11.002)