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Although I wouldn't classify it as "major" (certainly not these days), Rolemaster was definately a "system" and not merely a single game. The rules for Spacemaster and Cyber(something - I thought it was Cyberpunk but I might be mistaken) were based on the same system and you could model a variety of settings with that system.
I'll also note that ICE (the company that produced Rolemaster) has a new system out called HARP (High Adventure Role Playing). So far it only supports fantasy gaming but I'm getting the vibe that they'll expand into other genres if it succeeds.
I'll also note that ICE (the company that produced Rolemaster) has a new system out called HARP (High Adventure Role Playing). So far it only supports fantasy gaming but I'm getting the vibe that they'll expand into other genres if it succeeds.