We used the down-sampling and virtual tumor benchmarking approaches to compare MuTect against other commonly used methods: SomaticSniper21, JointSNVMix22 and Strelka23. Each method was tested in two configurations, standard (STD) and high confidence (HC), with thresholds chosen to produce similar false positive rates across the methods. For SomaticSniper (v1.0.0), we used the published configurations and for JointSNVMix (v0.7.5) we used a detection threshold of P(Somatic) ≥ 0.95 for STD and P(Somatic) ≥ 0.9998 for HC. For Strelka (v0.4.7) we used the recommended configuration with a quality score ≥ 15 for HC and ≥ 1 for STD.