An efficient tool dedicated to call somatic variants from whole-exome sequencing data using tumor and its matched normal tissue, plus a user-defined control panel of non-cancer samples. The program requires users to provide a control panel consisting of normal samples processed using similar procedures as the test sample (tumor), and uses this control to estimate site-specific error rates. Then, a binominal test is performed to determinate whether the ratio of altered reads of the tumor variant exceeds the background error rate. Compared with other methods, we showed superior performance of LoLoPicker with significantly improved specificity. The algorithm of LoLoPicker is particularly useful for calling variants from low-quality cancer samples such as formalin-fixed and paraffin-embedded samples.