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Now if there was one series that I would say absolutely needed to have the continuity scrapped and started all over, it would be the Fantastic Four. The four characters on this team are essential to comic book history and many people, myself included, would love to read it every month if it weren't for the mountain of continuity that needed to be known along with the almost overblown silliness that is at the core of the comic. While it would be fine to keep the silliness, Marvel should also keep it in check. Humor in the comic is totally fine but the sometimes ridiculous nature of the stories in Fantastic Four could be a huge turn off.
Many purists would detest the idea of renumbering the Fantastic Four, but it's simply a smart business plan on Marvel's part. People want to read your comic but they're intimidated by the big numbers and the fact that they can't open it up to a page and understand anything that is going on? Well, work with them and you can have a lifelong reader there. I'm sure many people really like what has been going on with Hickman's Fantastic Four/FF (Future Foundation for those not in the know) but if Marvel can make the book smaller in scope, or at least place focus solely on the family, it could be really good.
Likelihood of happening: I would say pretty high given Jonathan Hickman is confirmed to be leaving the Fantastic Four in favor of The Avengers, so there's an open position at one of Marvel's flagship titles.