All of the ideas I have read so far, with the exception of California as islands, pretty much assume that the US continent will be fundamentally unchanged after the apocalypse. I would suggest that the inevitable climate effects would possibly raise the sea level thus changing the coastlines and climate regions across the continent. The event could also redraw river channels, relocate fresh water basins (lakes, bayous, swamps and such), create new oases and deserts, and generally mess with the whole notion of 'let's get out that pre-war map and just go to where everything was before!'
Larger features would remain the same, but there could be enough difference that were the staring location someplace like Needles, CA, the terrain might be just recognizable (same big river near by), but enough different (natural lake from a collapsed watercourse, green belt around the lake, and so on) that you're really emerging into a new world again. This has the benefit of giving the design team a lot more freedom to alter the world significantly, but still rationally.
My hope is that, by incorporating this kind of overhaul of the known world, I will have the experience of discovering the places I thought I already knew, learning about what was changed and what remained the same, not just in the form of buildings, population and social order, but also about terrain, wildlife and natural resources. This, more than some other parts of Wasteland and Fallout 1/2, were what kept me playing and exploring.
A world changed just enough to be unpredictable, but hauntingly familiar, is just the world I hope to explore.