We will have a scrap piece of wood underneath the cutout, and screw our board down to the scrap.
Move the X, and Y to the desired zero location. (Our bottom left of the cut.)
Click on the number that represents the X.
Click Zero.
Click Set.
Click Ok
Notice that X is now Zero.
Do the same thing for the Y Axis.
Utilize the plate to zero out the Z. (Z-Zero is top of the board.)
Run your program.