Background: Amplification or overexpression of human epidermal growth factor receptor 2 (HER2) oncogene is present in about 15-20% of breast cancers & is a prognostic & predictive biomarker. Additional ERBB2/HER2 alterations have become apparent on tumor next generation sequencing (NGS), including activating kinase domain mutations & fusions. Methods: DNA NGS (592 gene panel or whole exome) data from 12,153 breast samples retrospectively reviewed for ERBB2 alterations with RNA whole-transcriptome sequencing (WTS) data available for 7289 (60%) samples. Gene fusions detected using the ArcherDx fusion assay or WTS. Clinicopathologic features were described including breast cancer subtype, age, & biopsy site. HER2 status determined according to 2018 ASCO-CAP guideline. Overall survival obtained from insurance claims & Kaplan-Meier estimates were calculated for defined patient (pt) cohorts. Statistical significance was determined using Chi-square & Wilcoxon rank sum tests. Results: ERBB2 mutations (ERBB2mts) were identified in 3.2% (n = 388) of tumors overall & most common in liver metastases (113/1972, 5.7%). ERBB2mts were found more in breast lobular tumors compared to ductal tumors (10 vs 2.1%, p < 0.001). HER2+ tumors had higher frequency of ERBB2mts compared to HER2- (4.3 vs 3%, p = 0.028). Tumors with score of 0 by immunohistochemistry demonstrated lower rate of ERBB2mts (0+ 2.2%, 1+ 3.5%, 2+ 4.5%, 3+ 3.45%, p < 0.05). Among HER2- tumors, ERBB2mts were present in 3.6% of hormone receptor (HR)+/HER2- & 1.9% of TNBC. Metastatic tumors had a higher rate of ERBB2mts compared to locoregional breast tumors (3.8 vs 2%, p < 0.001), with increased rates of activating mutations S310F (0.1 vs 0.0%, p < 0.05) & D769H (0.3 vs 0.1%, p < 0.05), & the resistance mutation L755S (1.2 vs 0.6%, p < 0.01). Compared to ERBB2-WT, ERRB2mts were associated with decreased ERBB2 transcripts levels in HER2+ samples (222 vs 441 transcripts per million [TPM], p < 0.001) & increased levels in HER2- samples (73 vs 35 TPM, p < 0.001). High tumor mutational burden (≥ 10 mut/Mb) &ERBB3 mutations were more common in ERBB2mts compared to ERRB2-WT (16.7 vs 7.7%, p < 0.001; 10.6 vs 0.8%, p < 0.001). ERBB2 fusions were rare (0.49%) with 97% occurring in HER2+ tumors. Of 8358 pts with outcome data, prognosis (HR 1.2, P = 0.06) & response to chemotherapy (HR 1.1, P = 0.42) was similar between pts with HER2- ERBB2mt&ERBB2-WT. Conclusions:ERBB2mts& fusions were observed in all breast cancer subtypes - more commonly in HER2+, metastatic, & lobular histology tumors - & did not influence prognosis. These alterations may reflect response to treatment pressures in HER2+ disease to reactivate HER2-mediated growth pathways following anti-HER2 therapy & may represent a targetable upregulated oncogenic pathway in HER2- disease. Ongoing identification of ERBB2 alterations may augment treatment options for breast cancer pts & clinical outcomes from this approach are under investigation.