We developed and benchmarked Exome Cancer Test v.2.0 (EXaCT-2), a novel whole-exome sequencing (WES) assay based on Agilent’s SureSelect hybrid-capture technology and expanded with custom probes targeting cancer-informative genomic regions. EXaCT-2 provides ~1,400 cancer genes with the depth of coverage typical of targeted panels, while achieving the genomic breadth to detect somatic copy number alterations (SCNAs), common cancer-related rearrangements, oncogenic viruses and B-cell receptor (BCR) clonotypes. Evaluated with a cancer patient cohort of 244 matched tumor/normal pairs and compared with clinically-validated results, EXaCT-2 achieved a mean sequencing depth of ~400× for critical cancer genes and ~100× for the remainder of the exome, with SCNA characterization showing improved boundary detection and overall segmentation. The assay demonstrated enhanced sensitivity for detecting sub-clonal, low-allele-frequency mutations missed by standard exome assays, such as mutations in GC-rich genes like KRAS. Analysis is performed by a modular, bespoke pipeline that leverages a workflow manager (Nextflow), in combination with containerized open-source tools. In addition to mutations and SCNAs, the pipeline reports common cancer rearrangements, hematologic oncogenic viruses, BCR clonotypes, and global molecular metrics, such as tumor mutational burden (TMB) and microsatellite instability (MSI). Collectively, these results establish EXaCT-2 as a comprehensive platform for integrated cancer genome profiling.