Abstract 2266: Development and validation of a cancer variant capture panel using the open-sourced CIViC database
Authors: Barnell Erica K. , Griffith Malachi , Campbell Katie M. , Krysiak Kilannin , McMichael Joshua F. , Coffman Adam C. , Kiwala Susanna , Griffith Obi L. 
Published: August 2018

Background: The Clinical Interpretations of Variants in Cancer database (CIViC) mitigates the variant interpretation bottleneck currently hindering clinical adoption of customized treatment plans for oncology patients. The knowledgebase stores evidence items derived from peer-reviewed publications detailing the therapeutic, prognostic, predisposing, and diagnostic implications of genetic variants in cancer. The knowledgebase is freely accessible without login requirements, fees, or exclusive access, making it uniquely able to attract contributions from volunteer domain experts. Here we present a method to create a dynamic capture panel derived from a community consensus of clinically-relevant variants using the CIViC knowledgebase.

Methods: Using curated Sequence Ontology IDs that specify the variant type (eg., missense mutation, fusion), we elucidated variants that could be evaluated by DNA-sequencing. A CIViC score was developed for each DNA-based variant to identify high-quality variants. This score takes into account the evidence level (eg. case-study, clinical data) and the curated trust rating of variant-associated evidence statements. Variants that attained a CIViC score &gt; 20 were eligible for the CIViC capture panel. CIViC-curated variant coordinates were used to design single molecule molecular inversion probes (smMIPs) for all eligible variants. Sequencing data from 27 samples across five tumor subtypes were compared using both the smMIPs assay and whole exome sequencing to assess panel performance.

Results: Of the 497 DNA-based variants in CIViC, 150 attained a CIViC score &gt; 20 points and were targetable via smMIPs assay. Of these 150 variants, 134 had at least one evidence item that was derived from a clinical study, thereby supporting the CIViC score's ability to identify high quality variants. We designed 2,124 smMIPs to assess the 150 CIViC variants. This required tiling protein-coding exons for 41 genes and developing targeted smMIPs for 95 single nucleotide variants, insertions, and deletions. The CIViC panel design showed extensive overlap with variants identified in the 27 samples using whole exome sequencing. Predicted overlap ranged from 2-12 variants per sample with an average of 4.1 variants per sample.

Discussion: Using expert crowd-sourced curation to drive production of the CIViC capture panel creates an impartial method for panel development. Future validation of the initial capture probe design will allow for automated development of probes for additional variants in the database as curated evidence increases.

Citation Format: Erica K. Barnell, Malachi Griffith, Katie M. Campbell, Kilannin Krysiak, Joshua F. McMichael, Adam C. Coffman, Susanna Kiwala, Obi L. Griffith. Development and validation of a cancer variant capture panel using the open-sourced CIViC database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2266.