Not the best title or description so let me begin with an example:
Your RB1 has great WR-based ratings, so much so that you could play him at WR if you wanted to. I'm a Pats fan so I am thinking about a guy like Shane Vereen. He's a solid runner and a great receiver out of the backfield...but unlike many pass-catching RBs, he can actually line up wide and run downfield routes. This sets up a situation where I can bring out 21 personnel (2 RBs, 1 TE, 2 WR) but instead of lining up in a 2-back formation, I line the RB out wide as a WR and leave the FB in the backfield as a runner or pass blocker.
So how to do this in the game? The only way I could find to do it would be to use the Depth Chart overrides to make some changes to one of the personnel groups. If I alter, say, Singleback Slot Strong (11 personnel) so that RB1 plays WR3 and FB1 plays RB1, now I have the personnel and formation I want.
However...
I wonder if the game will look at that and say "oh, he's got 2 RBs, 1 TE, and 2 WRs..." because that's the actual personnel and react accordingly OR if it will simply say "oh, he called a play that uses the Singleback Slot Strong (11 personnel) formation...so he's got 1 RB, 1 TE, and 3 WRs..." and not pay attention to the actual personnel.
I would want the former because I want the defense to react to the fact that I have 2 RBs on the field. In the latter situation, no advantage is gained by the substitution.