Background: Approximately 15-20% of invasive breast carcinomas (BCA) show HER2/ERBB2 gene amplification which determines eligibility for treatment by targeted therapy. Traditionally, HER2 status is determined by IHC and FISH. NGS methods can be used to assess HER2 status in clinical practice but concordance with IHC/FISH is not well established. We report our experience using NGS for the assessment of HER2 amplification in conjunction with the detection of potentially targetable mutations. Methods: BCA samples ( > 10% tumor) were analyzed in a CLIA-certified lab using a hybrid capture-based NGS assay (“MSK-IMPACT”) designed to detect somatic genetic alterations in 341 genes, including copy number alterations. Tumor percentage and concurrent IHC/FISH results were recorded (using ASCO/CAP 2013 guidelines). Criteria for amplification by NGS were defined as a fold change (FC) ≥ 2, p-value < 0.05. Results: A total of 133 BCA samples (63 primaries, 70 mets) were analyzed. Compared to the combined IHC/FISH methodology, ERBB2 amplification status by NGS had an overall concordance of 97% (129/133) (sensitivity = 82%, specificity = 100%, PPV = 100%). Discordant cases showed low tumor purity, heterogeneous IHC staining, and/or low level amplification by FISH. One sample status post trastuzumab was negative by IHC but ERBB2 amplified by FISH (ratio 4.0) and NGS (FC 2.3). The assay also uncovered somatic alterations in 133 cancer genes including TP53, PIK3CA, CDH1 and ESR1. ER and PR IHC results were available for 94 cases; 1/13 triple negative cases showed an actionable PIK3CA E542K mutation. Of the 22 ERBB2 amplified cases, 6 had actionable PIK3CA mutations (H1047R or E545K); 4/6 were metastatic lesions in patients previously treated with trastuzumab. Conclusions: HER2 status can be reliably determined by hybrid capture NGS methods and allows the concurrent testing for other potentially actionable genomic alterations, particularly in limited material. Samples with low tumor content, heterogeneity and low level amplification may result in false negatives.