Oh boy, that's a loaded question
I guess it would have to be a game that fell far below expectations, something that seriously hurt a brand.
There are a lot of contenders: Aliens Colonial Marines, Duke Nukem Forever, Resident Evil 6 (apologies, Wright), Fable 3, etc.
I might have to go with Halo 4. It undermined the legacy of what I consider the best all-around shooting series. It brought the worst parts of Call of Duty into Halo, both in multiplayer and single player.