Described herein is a mutation that confers resistance to the treatment with a BTK inhibitor. Described herein is a modified PLCγ2 polypeptide that is modified at amino acid position 742, 845, or 1140 and the modified PLCγ2 polypeptide exhibits decreased inhibition (e.g., resistance) to a covalent and/or irreversible BTK inhibitor. Described herein are diagnostic methods for detecting the modified polypeptide and nucleic acid encoding the modified polypeptide and applications of the methods thereof. Described herein are compositions, combinations, and kits containing the modified polypeptide and methods of using the modified polypeptide. Also described herein are methods of using the modified polypeptide as screening agents for the identification and design of inhibitors of PLCγ2.