Sherloc: a comprehensive refinement of the ACMG–AMP variant classification criteria

• Published in: Genetics in medicine Vol. 19; no. 10; pp. 1105 - 1117
• Main Authors: Nykamp, Keith, Anderson, Michael, Powers, Martin, Garcia, John, Herrera, Blanca, Ho, Yuan-Yuan, Kobayashi, Yuya, Patil, Nila, Thusberg, Janita, Westbrook, Marjorie, Topper, Scott
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2017; Elsevier Limited; Nature Publishing Group
• Subjects: 631/208/1516; 631/208/2489/1512; 631/208/726/649; Biomedical and Life Sciences; Biomedicine; Classification; Genetic Testing - standards; Genetic Variation - genetics; Genome, Human; Genomics - methods; High-Throughput Nucleotide Sequencing; Human Genetics; Humans; Laboratory Medicine; Original; original-research-article; Sequence Analysis, DNA - standards; Software; clinical interpretation; variant classification; ACMG laboratory guideline; clinical genetic testing; variant interpretation
• ISSN: 1098-3600; 1530-0366; 1530-0366
• DOI: 10.1038/gim.2017.37

Purpose The 2015 American College of Medical Genetics and Genomics–Association for Molecular Pathology (ACMG–AMP) guidelines were a major step toward establishing a common framework for variant classification. In practice, however, several aspects of the guidelines lack specificity, are subject to varied interpretations, or fail to capture relevant aspects of clinical molecular genetics. A simple implementation of the guidelines in their current form is insufficient for consistent and comprehensive variant classification. Methods We undertook an iterative process of refining the ACMG–AMP guidelines. We used the guidelines to classify more than 40,000 clinically observed variants, assessed the outcome, and refined the classification criteria to capture exceptions and edge cases. During this process, the criteria evolved through eight major and minor revisions. Results Our implementation: (i) separated ambiguous ACMG–AMP criteria into a set of discrete but related rules with refined weights; (ii) grouped certain criteria to protect against the overcounting of conceptually related evidence; and (iii) replaced the “clinical criteria” style of the guidelines with additive, semiquantitative criteria. Conclusion Sherloc builds on the strong framework of 33 rules established by the ACMG–AMP guidelines and introduces 108 detailed refinements, which support a more consistent and transparent approach to variant classification.