next generation sequencing is extensively applied to catalogue somatic mutations in cancer in research settings and increasingly in clinical settings for molecular diagnostics guiding therapy decisions somatic variant callers perform paired comparisons of sequencing data from cancer tissue and matched normal tissue in order to detect somatic mutations the advent of many new somatic variant callers creates a need for comparison and validation of the tools as no de facto standard for detection of somatic mutations exists and only limited comparisons have been reported we have performed a comprehensive evaluation using exome sequencing and targeted deep sequencing data of paired tumor normal samples from five breast cancer patients to evaluate the performance of nine publicly available somatic variant callers ebcall mutect seurat shimmer indelocator somatic sniper strelka varscan 2 and virmid for the detection of single nucleotide mutations and small deletions and insertions we report a large variation in the number of calls from the nine somatic variant callers on the same sequencing data and highly variable agreement sequencing depth had markedly diverse impact on individual callers as for some callers increased sequencing depth highly improved sensitivity for snv calling we report ebcall mutect virmid and strelka to be the most reliable somatic variant callers for both exome sequencing and targeted deep sequencing for indel calling ebcall is superior due to high sensitivity and robustness to changes in sequencing depths.