Hard to say any single one is "the best ever", there's so much variance in the genre and depends what the player is looking for. There's a lot I never played so can't vouch for personally.
For me the original Papyrus Indy Car Racing / IR2 and Nascar Racing series were almost life altering. I had not experienced any game/sim up to that point that drew me in and required that kind of focus. The earlier iterations may not be best all time when judged today, but I think should be high on the "most significant" list.
Best all time focusing on a single series/genre: I'd say probably Nascar Racing 2003 and GTR2. I have not played ACC so can't comment on that, but it's probably too early to say whether it will also become legendary like NR2003 and GTR2. Maybe the current F1 series deserves a spot on the podium (sorry, had to) for its scalability and inclusion of a genuine career mode.
Best "jack of all trades": That's tough - I'll say Assetto Corsa, but RF2 and something like PCars2 cover more ground (stock cars, ovals, etc - note I'm not necessarily referring to how WELL they do that). AC does a better job of being a more polished, cohesive package (that's more vs RF2) and the mod support has extended its breadth by a wider margin. If not for the mod support, I'd rank AC lower as the "stock" content - particularly tracks, is somewhat limited. I never played AMS or AMS2, RaceRoom, and plenty of others so can't comment on them.
Most significant "franchise" in the history of sim racing: Gran Turismo. Whether you consider it a "sim" or not, GT as a series has probably introduced more people to anything resembling "serious" driving sims/games since its inception than any other game/sim or series. Its probably been the "gateway" sim/game to anything deeper, though I suppose Project Cars 1 and 2 in recent years sold in big numbers as well (also Forza Motorsport in the XBox ecosystem).
Best multiplayer - I supposed has to be iRacing due to to its structure and wide range of genres. I had only limited time in iRacing and it was both the worst and best sim racing experiences I've ever had. My current work/life situation doesn't really fit with the time and money commitment iRacing requires to be worthwhile at the moment. That may change at some point.
The sim that I WANT to be the best but just can't seem to get there: RFactor 2. To me it has the best physics/FFB of any sim I've ever driven - usually. It covers every genre of racing I have any interest in. S397 have done a good job adding content, their current track models are outstanding, lots of good work has been done and more is on the way. BUT there's been so much fixing one thing and something else breaks along the way, and the balance of car/track/AI is so inconsistent I fear it will never be fully smoothed out. I've spent far more hours testing and keeping spreadsheets of what has been good and not so good for me than just racing and enjoying it, it's like a second job sometimes.