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Cancers often have reduced allelic diversity because of loss of heterozygosity (LOH). Therefore, tumors arising in patients heterozygous for a functional and a loss-of-functon (LoF) allele may lose the functional allele, rendering them sensitive to allele-specific therapies. To discover such alleles, we mined the 1000 Genomes dataset for SNVs causing protein truncation through base substitution, indels or splice site disruptions, resulting in 60 LoF variants in 60 genes. The LoF splice site variant rs3892097 in CYP2D6 was selected as it resides in a genomic region undergoing LOH in different tumor types, is highly polymorphic with over 135 allelic variants, and metabolizes~ 25% of clinically used drugs. We generated cell systems and screened anticancer agents in clinical use or in clinical trials for differential toxicity, and Talazoparib and MK-8776 were shown to exhibit consistent cytotoxicity against hepatocellular …