A computational method for detecting somatic variants using high throughput sequencing data from unpaired tissue samples. We evaluate the performance of the method using genomic data from synthetic and real tumor samples. SomVarIUS identifies somatic variants in exome-seq data of ~150X coverage with at least 67.7% precision and 64.6% recall rates, when compared with paired-tissue somatic variant calls in real tumor samples. SomVarIUS can be useful in a variety of clinical or research settings, where matched normal samples are not yet routinely collected (e.g. precision medicine initiatives) or for archival samples (e.g. FFPE and fresh frozen tumor samples stored in the tissue banks).