A method for robustly and accurately detecting rare DNA mutations in tumor samples is critical to cancer research. Because many clinical tissue repositories have only FFPE-degraded tumor samples, and no matched normal sample from healthy tissue available, being able to discriminate low frequency mutations from background noise in the absence of a matched normal sample is of particular importance to research. Current state of the art variant callers such as GATK and VarScan focus on germline variant calling (used for detecting inherited mutations following a Mendelian inheritance pattern) or, in the case of FreeBayes and MuTect, focus on tumor-normal joint variant calling (using the normal sample to help discriminate low frequency somatic mutations from back ground noise). We present Pisces, a tumor-only variant caller exclusively developed at Illumina for detecting low frequency mutations from next generation sequencing data. Pisces has been an integral part of the Illumina Truseq Amplicon workflow since 2012, and is available on BaseSpace and on the MiSeq sequencing platforms. Pisces has been available to the public on github, since 2015. (https://github.com/Illumina/Pisces) Since that time, the Pisces variant calling team have continued to develop Pisces, and have made available a suite of variant calling tools, including a ReadStitcher, Variant Phaser, and Variant Quality Recalibration tool, to be used along with the core variant caller, Pisces. Here, we describe the Pisces variant calling tools and core algorithms. We describe the common use cases for Pisces (not necessarily restricted to somatic variant calling). We also evaluate Pisces performance on somatic and germline datasets, both from the titration of well characterized samples, and from a corpus of 500 FFPE-treated clinical trial tumor samples, against other variant callers. Our results show that Pisces gives highly accurate results in a variety of contexts. We recommend Pisces for amplicon somatic and germline variant calling.