smMIPs sequencing for validation of open-sourced CIViC Annotation Pipeline (OpenCAP)

We used the Clinical Interpretations of Variants in Cancer database (CIViC; https://civicdb.org) to develop an Open-sourced CIViC Annotation Pipeline (OpenCAP; https://opencap.org). OpenCAP provides methods to identify variants within the CIViC database, build probes for variant capture, employ probes on prospective samples, and link somatic variants to CIViC clinical relevance statements. OpenCAP was tested using single-molecule molecular inversion probe (smMIP) capture design on 27 cancer samples from 5 tumor types. In total, 2,027 smMIPs were designed to target 111 eligible CIViC variants (61.5 kb of genomic space). When compared to orthogonal sequencing, CIViC smMIP sequencing demonstrated a 95% sensitivity for variant detection (n=61/64 variants). Variant allele frequencies for variants identified on both sequencing platforms were highly concordant (Pearson correlation=0.885; n=61 variants). Moreover, for individuals with paired tumor/normal samples (n=12), 182 clinically relevant variants missed by orthogonal sequencing were discovered by CIViC smMIPs sequencing.