Changes in the quantity of genetic material, known as somatic copy number alterations (CNAs), can drive tumorigenesis. Many methods exist for assessing CNAs using microarrays, but considerable technical issues limit current CNA calling based upon DNA sequencing. We present SynthEx, a novel tool for detecting CNAs from whole exome and genome sequencing. SynthEx utilizes a “synthetic-normal” strategy to overcome technical and financial issues. In terms of accuracy and precision, SynthEx is highly comparable to array-based methods and outperforms sequencing-based CNA detection tools. SynthEx robustly identifies CNAs using sequencing data without the additional costs associated with matched normal specimens.