If you remove a file called, say, fred, then the user "fred" will lose all of his mail. There should be no other consequence. If fred gets new mail, another file called fred will appear. I do stuff like that...usually because fred has some cron job sending him mail once an hour or something. So rather than repeatedly deal with it, I then create a ~fred/.forward containing "nobody".

But removing stuff in /var/spool/mail will not usually free space in /usr. With a really screwy symlink, it is possible...but are you sure that your system is set up like that?