Background: The accurate screening of tumor genomic landscapes for somatic mutations using high-throughput sequencing involves a crucial step in precise clinical diagnosis and targeted therapy. However, the complex inherent features of cancer tissue, especially, tumor genetic intra-heterogeneity coupled with the problem of sequencing and alignment artifacts, makes somatic variant calling a challenging task. Current variant filtering strategies, such as rule-based filtering and consensus voting of different algorithms, have previously helped to increase specificity, although comes at the cost of sensitivity. Methods: In light of this, we have developed the NeoMutate framework which incorporates 7 supervised machine learning (ML) algorithms to exploit the strengths of multiple variant callers, using a non-redundant set of biological and sequence features. We benchmarked NeoMutate by simulating more than 10,000 bona fide cancer-related mutations into three well-characterized Genome in a Bottle (GIAB) reference samples. Results: A robust and exhaustive evaluation of NeoMutate's performance based on 5-fold cross validation experiments, in addition to 3 independent tests, demonstrated a substantially improved variant detection accuracy compared to any of its individual composite variant callers and consensus calling of multiple tools. Conclusions: We show here that integrating multiple tools in an ensemble ML layer optimizes somatic variant detection rates, leading to a potentially improved variant selection framework for the diagnosis and treatment of cancer. [ABSTRACT FROM AUTHOR]