5551 Background: Tumors with genomic alteration (GA) of BRCA1 or BRCA2 ( BRCA) may be more sensitive to platinum (Pt) therapies and PARP inhibitors (PARPi). However, secondary reversion mutations (revGA) can arise that may restore BRCA function and underlie reduced sensitivity to Pt compounds or PARPi. Methods: DNA extracted from FFPE tumor tissue or blood samples obtained during routine clinical care for patients with predominantly relapsed, refractory or metastatic breast cancer (10967) or ovarian/peritoneal cancer (8352) was analyzed by hybrid-capture, next-generation sequencing for all classes of GA: base substitutions, indels, rearrangements, and copy number changes. RevGA were any GA that could restore the reading frame if in cis with a nonsense or frameshift (fs) GA. Results: 1900/19329 (9.8% ± 0.4%) tumors had ≥1 deleterious BRCA GA. 38 samples harbored potential revGA in BRCA1 (16) or BRCA2 (22): breast carcinoma (Ca) (21), ovarian or peritoneal serous Ca (10), ovarian or peritoneal adenocarcinoma (3), and ovarian epithelial Ca NOS (4). 35/38 sequenced samples were metastases. All potential revGA were somatic and fell into 3 classes: overlapping indel (21), compensatory fs (6), and missense mutation (11). One case harbored both an overlapping indel and a missense mutation with potential to revert a nonsense alteration. For 6 patients, testing of multiple tissue samples reveals the acquisition of revGA over time. RevGA are generally observed at allele frequencies lower than the deleterious GA they may revert. Clinical histories for patients with reversion mutations will be presented. Conclusions: Genomic profiling of breast and gynecological carcinomas, using either tissue or liquid biopsies, reveals potential revGA that may restore some level of BRCA function. RevGA, although rare, can be acquired during the course of treatment. We identified potentially compensatory missense, fs and indel mutations with CGP. Comparison of allele frequencies suggests that revGA often arise as subclones. The acquisition of a revGA over time can be observed through testing of multiple samples, either tissue or liquid biopsy.