Background: Human epidermal growth factor receptor 2 (HER2) amplification is now a highly actionable alteration for patients with colorectal cancer (CRC) with distinct combination therapies. Recent studies have shown that oncogenic KRAS, BRAF, and PIK3CA mutations, may serve as biomarkers of response to HER-directed treatments such as Trastuzumab and Tucatinib/Pertuzumab. In this study, we investigated the incidence of MAP kinase and mTOR pathway alternations in patients with HER2-amplified CRC. Methods: The cBioPortal for Cancer Genomics was utilized to obtain data and graphics on HER2 amplification in CRC. cBioPortal was queried to select 21 published studies that contain CRC specimens (assessed April 2023). Clinical, specimen, copy number alteration (CNA), and somatic mutation data of each study were downloaded and aggregated across all studies, followed by filtering, standardization, and harmonization to generate ~30 analysis-ready fields encompassing demographic variables, HER2 amplification, and KRAS/NRAS/PIK3CA/BRAF mutations. Results: Among a pool of 4822 CRC patients with known gender, 44.4% (2139) were female and 55.6% (2683) were male. The incidence of HER2 amplification in the overall cohort was 2.6% (123/4822) and was noted to be higher in males (3.1%, 82/2683) than in females (1.9%, 41/2139). The incidence of HER2 amplification was highest in Asian CRC patients (3.9%, 9/228), followed by Black CRC patients (3.0%, 9/298), and then Caucasian CRC patients (2.7%, 57/2118). Rates of HER2 amplification were similar in the colon and the rectum at 2.6% (61/2360 and 26/1015, respectively). After analyzing rates of concurrent MAPK and mTOR pathway mutations in patients with HER2-amplified CRC, KRAS mutations were noted to be the most common mutation in HER2-amplified colon cancer (27.9%, 17/61), but were less common in HER2-amplified rectal cancer (7.7%, 2/26). PIK3CA mutations were also common, with an incidence of 13.1% (8/61) in HER2-amplified colon cancer and 7.7% (2/26) in HER2-amplified rectal cancer. NRAS mutations occurred at comparable, low rates in HER2-amplified colon and rectal cancer, at 3.3% (2/61) and 3.8% (1/26) respectively. No BRAF mutations were reported in either disease group. Conclusions: In this study, we identified that MAPK and mTOR pathway alterations are relatively common among patients with HER2-amplified CRC. These somatic events appear to be more common in HER2-amplified colon cancer than rectal cancer. Next generation based molecular profiling is recommended to identify potential resistance mechanisms before initiation of HER2-directed therapy.