Optimization of multigene analysis of tumor samples

A method of separating targeted nucleic acid molecules from a sample, comprising:

• combining, in the same solution, at least two different bait sets and a library comprising a plurality of nucleic acid molecules to form a plurality of nucleic acid hybrids, wherein the at least two different bait sets each comprise one or more bait molecules comprising a binding entity and a sequence configured to capture a target sequence, wherein the nucleic acid hybrids comprise a target nucleic acid molecule and a bait molecule, and wherein the at least two different bait sets comprise:
• a first bait set comprising a bait molecule comprising a sequence configured to capture a target sequence comprising a point mutation, and
• a second bait set comprising a bait molecule comprising a sequence configured to capture a target sequence comprising a structural breakpoint;
• and
• separating the plurality of nucleic acid hybrids from a remainder of the library.