Abstract Precision oncology is dependent upon the matching of tumor variants to relevant knowledge describing the clinical significance of those variants. We recently developed the Clinical Interpretations for Variants in Cancer (CIViC; civicdb.org) crowd-sourced, expert-moderated, and open-access knowledgebase. CIViC provides a structured framework for evaluating genomic variants of various types (e.g., fusions, SNVs) for their clinical utility based on therapeutic, prognostic, predisposing, diagnostic, and functional evidence. CIViC has a documented API for accessing CIViC records: Assertions, Evidence, Variants, and Genes. Third-party tools that analyze or access the contents of this knowledgebase must programmatically leverage this API, often reimplementing redundant functionality in the pursuit of common analysis tasks that are beyond the scope of the CIViC web application. We recently published CIViCpy v1.0 (civicpy.org), a software development kit (SDK) for extracting and analyzing the contents of the CIViC knowledgebase. CIViCpy enables users to query CIViC content as dynamic objects in Python. Here we highlight new features and informative analyses introduced since the original publication. New features include an extended variant search functionality that supports queries by variant name, HGVS, and ClinGen Allele Registry ID (CAID). In addition to the CIViC-native GRCh37 coordinates, CIViCpy now supports variant queries from multiple alternative human genome builds, including hg18 and GRCh38. CIViCpy also includes multiple easy-to-use tools for straightforward installation in a variety of compute environments. A commonly requested feature is the annotation of user-provided variants in Variant Call Format (VCF) with CIViC data. CIViCpy now provides convenient methods, including a command line interface (CLI), for performing this task. We illustrate the use of newly added features by annotating pan-cancer VCF files from The Cancer Genome Atlas (TCGA). We show that CIViCpy is able to quickly and efficiently annotate patient variants in the context of the reported disease type, appending data about the associated CIViC Evidence and Assertions to the provided VCF files. The clinical interpretation of genomic variants in cancers requires high-throughput tools for interoperability and analysis of variant interpretation knowledge. These needs are met by CIViCpy, an SDK for downstream applications and rapid analysis. The new features discussed here allow users to easily incorporate CIViC knowledge into their variant annotation pipelines. CIViCpy (civicpy.org) is fully documented, open-source, and freely available online. Citation Format: Susanna Kiwala, Alex H. Wagner, Adam C. Coffman, Joshua F. McMichael, Kelsy C. Cotto, Thomas B. Mooney, Erica K. Barnell, Kilannin Krysiak, Arpad M. Danos, Jason M. Walker, Obi L. Griffith, Malachi Griffith. Adding CIViC knowledge to variant annotation pipelines with CIViCpy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5462.
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