What a coincidence, I just played that mission yesterday (on my 3rd playthrough). It doesn't have the same emotional impact the 3rd time of course, but I remember that being a pretty sad moment, although they probably could of let it hang just a little longer to make it more effective. Also, if there was one character who should go down fighting, it should be Grunt. There were a few times in ME3 that I came close to, or actually did, start crying, which is something I'm not used to and was not expecting at all when starting that game. The most impactful one was the one people have already mentioned here. I even had that moment spoiled for me but that still didn't help me get through it.
They couldn't go too far back into the past if they still wanted humans in the game. I think they were only relevant on a galactic scale for something like 26 years when ME1 starts. If it was a prequel with a human as the main character, then it would probably be centered around the First Contact War, which might be interesting.
Speaking of years, am I the only one confused by how people in the Mass Effect universe use years as a unit of time? Almost all the planets have different orbital periods than Earth. Maybe each species translator automatically does the math and gives you the converted time for their homeworld, or something. I don't know. I think about this stuff a lot.