To me game of the year needs to be a title that pushes boundaries. That excels at both being a good new IP or sequel to a franchise but at the same time takes risks and offers something new.
That being said Mass Effect 3, Uncharted 3 and Portal 2 are most likely not going to be the games of the year. I think they will all be nominated for sure, but I don't think they will win.
Skyrim, LA Noire and Deus EX I believe to have the strongest chance of winning it this year. Skyrim like any other Elder Scrolls game is a huge undertaking of a project that usual pushes the boundaries of what you can do with in a game and the size of the world you can explore. Even with the bugs they are masterpieces. LA Noire is pushing storytelling further in a GTA style game with a focus on characters that has never been seen before. Deus EX is the wild card here, the first one was awesome with one of the most complex stories I have ever seen in a videogame.