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Background: ERBB2 is an EGFR family member encoding the ligand independent receptor tyrosine kinase HER2. ERBB2 amplification is well understood to drive oncogenesis, with breast carcinoma as the exemplar. To explore the oncogenic potential of ERBB2 non-amplification genomic alterations, we have retrospectively reviewed the genomic profiles and clinical history of 37 patients with different cancers harboring such alterations Materials and Methods: We explored the spectrum of ERBB2 somatic mutations across of 2,250 patients that underwent hybrid-capture based comprehensive genomic profiling (CGP) utilizing next-generation sequencing (NGS) at a single CLIA-certified, CAP-accredited, New York Statue Regulated central laboratory (Foundation Medicine, Inc.). The population consists of patients from 5 different cancer centers. This retrospective review was IRB approved. Cancer type, ERBB2 mutation type, co-existing mutations, number of chemotherapy lines, date of metastasis, relapse date and deceased date were collected. Clinically relevant genomic alterations were denoted as those suggesting benefit from an FDA-approved targeted therapy or mechanism driven clinical trial. Results: Out of the 37 patients with ERBB2 mutations, 18/37 (49%) were males, and 19/37 (51%) were females. Among cancer types, 12/37(32%) had lung cancer, colon 6/37(16%), bladder 5/37(13.5%), breast 4/37(11%), and other cancers 6/37 (6%). The median number of chemotherapy lines administered among all patients was 3. The alterations in ERBB2 were distributed as follows: 54% (20/37) in the kinase domain, 30%(11/37) in the extracellular domain (ECD) and 11% (4/37) in the non-kinase intracellular domain, and 5% (2/37) truncations. Of ECD domain mutations, 81% (9/11) were at the S310 position. 198 non-ERBB2 alterations co-occurred in this cohort, 89 of which were clinically relevant genomic alterations. In this population, colorectal carcinoma had the highest mutational load followed by duodenum/jejunum, bladder, skin malignancies, gallbladder, cervix, tonsil, breast and stomach. We partitioned overall survival (OS) into two parts and expressed it as the sum of progression free survival (PFS) and survival post-progression (SPP) and it was calculated among the deceased patients 18/37(49%). The median patient survival in this cohort was 25 months. Among individual tumor types, lung cancer had the lowest OS, which was 9 months (M), followed by breast (35 M), colon (41 M), and bladder (44 M). Conclusion: In this retrospective study the incidence of ERBB2 non-amplification alterations in a variety of solid tumors was 1.6%. Outcomes data in this small cohort will be assessed for prognostic implications of these alterations, and any treatment episodes with HER2- targeted therapy will be reported. A prospective histology-independent, aberration-specific study is necessary to decipher the effect of anti-HER2 targeted against these alterations. Citation Format: Sharon Wesley Dev Sahadevan, Zachary Chalmers, Garret M. Frampton, Navneet Dhillon, Kim Kramer, Philip J. Stephens, George W. Daneker, Jeffrey S. Ross, Vincent A. Miller, Maurie Markman, Siraj M. Ali, Ricardo H. Alvarez. Clinical evaluation of patients with advanced solid tumors harboring ERBB2-somatic mutations. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A80.