Amplification of the ERBB2 or HER2/Neu in colorectal cancer leads to downstream activation of the PI3K-AKT-ERK mediated pro-proliferative signaling cascade. Targeting HER2 with a humanized monoclonal antibody, such as trastuzumab or pertuzumab, initiates antibody-dependent cellular cytotoxicity, cell-cycle arrest and impaired DNA repair leading to apoptosis. The HER2-del16 splice variant is a tumor-specific event that removes the extracellular juxtamembrane domain and promotes resistance to HER2-targeted therapy. In this precision medicine molecular case report, we describe the disease course of a patient diagnosed with metastatic colorectal cancer that harbored HER2 amplification with concurrent HER2-del16 splice and TP53 missense mutations. Multiple genomic events identified in this patient made the tumor particularly aggressive and resistant to cytotoxic as well as to HER2-targeted chemotherapy. This case underlines the existing challenges in determining and optimizing individualized therapy in the context of rare molecular events, as the disease response was affected by diverse parameters including alterations in multiple tumor suppressors and proto-oncogenes, and discrepancies in preclinical and clinical data on targeted therapy response.