With the growing use of genetic testing in medicine, the question of when genetic findings should be reinterpreted in light of new data has become inescapable. The generation of population and disease-specific data, development of computational tools, and new understandings of the relationship of specific genes to disorders can all trigger changes in variant classification that may have important implications for patients and the clinicians caring for them. This is a particular concern for patients from groups underrepresented in current reference datasets, since they have higher rates of uncertain findings. Here we identify the challenges to implementing a systematic approach to variant reinterpretation and propose solutions. In particular, we address (a) the infrastructure needed to support implementation of systematic variant reinterpretation, (b) the issues around obtaining consent from patients for reinterpretation, (c) the process for triggering reinterpretation, (d) pathways for the flow of reinterpreted data, (e) considerations for how to cover the costs of reinterpretation, and (f) practical issues related to implementation of processes and policies that address these issues, including the importance of a fixed duration during which there is an expectation that variants will be reinterpreted.