I am assuming a tunnel under the Georges River is out of the question because of the cost. But the F6 could go into a tunnel where it comes off the bridge on the northern side of the Georges River. Then it could go underground and join up underground with the other existing and planned motorways. If the F6 is in a tunnel, it doesn't have to go into the planned corridor where the water table could cause complications. It can go anywhere.
In a minimalist implementation there would be no interchanges (points where traffic comes on or off the motorway) in the St George area at all. If the through traffic goes underground, the existing surface roads should be enough for drivers travelling into, out of and within the St George area.
If there are going to be interchanges, either from the start or further into the future, then it is probably best to route the F6 along the Princes Highway, the existing major aterial road through the St George area. That would make it easier to build interchanges where the existing traffic flows are. There would also need to be enough interchanges. If there are too few interchanges (but more than none), that would focus too much traffic on those interchanges. And spaghetti junctions are unsightly. It would be much better to have a number of discreet ramps in or near the Princess Highway.