I've been thinking about this thread for a while, and I think it's hard to come up with a better answer than 1492. The fall of the Roman Empire was important, but there's nothing more era-ending than adding two new continents to the equation (of what Europeans knew about).
Fair point, actually. However, I think "Middle Ages" is used in such a Euro-centric way that the fall of the Byzantine Empire (an empire that based its entire existence and purpose on God's will and Orthodox Christianity, perfectly encapsulating the "Middle Ages" to me) is a pretty monumental shift ... even if it was a client state when it finally fell.