The death of Hawke's mother.
The circumstances were twisted and horrible to be sure, but that same death wouldn't've had the same impact if the game hadn't been as well-written as it was. Dragon Age II is the only game I've seen successfully establish a family dynamic and rounding out of characters within those dynamics.
The first time I played through, I was a warrior. Carver's death didn't surprise me. I could tell he would have lived if I'd chosen to play a mage, but Bethany would have died. It didn't hit me, though, because it was early in the game and I barely knew the characters.
I took Bethany into the Deep Roads. When she died of Darkspawn plague, it caught me by surprise. I'd had her with me almost constantly to that point because I liked her character and she was useful as a support mage. It was at her death I realized I'd taken the fact that I was the protagonist for granted. I'd forgotten that in this game, I wasn't a Grey Warden, and neither was she.
But then when Hawke's mother died, I wanted to cry. Through dialogue, I'd comforted her after my siblings' deaths. I'd coyly encouraged her when she told me she had found a suitor. I'd definitely established a maternal relationship with her, and seeing her die in such a horrible way was the most tragic thing I'd seen in a game.
And when Gamlen apologized to me and said he wanted us to start over, given that we were the only family the other had, I accepted with gratitude.
It disappoints me so much when gamers complain about Dragon Age II. I really feel they've missed the point.