Background: Human epidermal growth receptor 2 (HER2) is a well-known oncogenic drive gene with multiple targeted therapeutic options. In this study, we aim to assess the landscape of HER2 alterations in solid tumors and evaluate the feasibility of circulating tumor DNA (ctDNA) tested by next-generation sequence (NGS) as a tool to detect HER2 alterations. Methods: Alterations of HER2 by NGS (Illumina NextSeq 500) were queried in 3D Medicines database. The mean depth of tissue and circulating tumor DNA (ctDNA) test was 500X and 5000X, respectively. 11,013 patients tested using tumor tissue and 6,970 patients tested using ctDNA were included in this analysis. Results: Of 11,013 patients tested using tumor tissue, any HER2 and known or likely deleterious HER2 mutations were identified in 739 (6.7%) and 531 (4.8%) patients, respectively. Of 531 patients who carried known or likely deleterious HER2 mutations, 263 (49.5%) had HER2 amplification and 259 (48.8%) had single nucleotide variations (SNVs). Across all tumor types, breast cancer was found to have the highest frequency of HER2 amplification (14.9%, 48/323), followed by gastric cancer (6.6%, 31/470) and biliary tract cancer (5.8%, 33/571). Moreover, 11% (8/73) of duodenal cancer, 4.5% (7/154) of urothelial cancer, 3.8% (18/470) of gastric cancer, 3.1% (142/4555) of lung cancer, 2.9% (17/571) of biliary tract cancer, 2.8% (44/1562) of colorectal cancer and 2.7% (9/323) of breast cancer carried known or likely deleterious HER2 SNVs. Of 6970 patients tested using ctDNA, any HER2 and known or likely deleterious HER2 mutations were identified in 592 (8.5%) and 277 (4.0%) patients, respectively. In the ctDNA cohort, 15.7% (36/230) of breast cancer and 3.1% (5/161) of biliary tract cancer carried HER2 amplification. However, 11.6% (20/173) of gastric cancer had HER2 amplification tested by ctDNA which was higher than that tested using tissue. Furthermore, 5.6% (13/230) of breast cancer, 4.5% (2/44) of urothelial cancer, 3.4% (6/173), 2.5% of biliary tract cancer and 2.0% (94/4586) lung cancer harbored known or likely deleterious HER2 SNVs in ctDNA cohort. Conclusions: HER2 alterations existed across tumor types and the landscape of genomic alterations in HER2 gene varied according to different type of tumor. In addition, ctDNA can be used as a potential tool to detect HER2 alterations.