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Key Clinical Message Post‐radiation angiosarcoma of the breast is a rare complication associated with a poor prognosis. This case reports the first loss of function mutation in TSC1 in breast radiation‐induced angiosarcoma and illustrates the utility of evaluating these markers to identify potential therapeutic targets. Abstract Post‐radiation angiosarcoma of the breast is rare and associated with a poor prognosis. This case presents the first loss of function mutation in TSC1 in breast radiation‐induced angiosarcoma. Evaluation of these markers can aid in identifying potential therapeutic targets.