The TransAm has been run for decades, and there were even races in the 1920s (the famous "Bunion Derby") and again in the early 1990s.  A web search will yield much history, here's a brief summary:  https://www.outsideonline.com/2129171/brief-history-run-across-america  The course is open, and of course evolves with development of the road system, but the end points are fixed:  City Hall in San Francisco and New York City Hall (note that the TransAm footraces were Los Angeles to New York).

William Johnson submitted this route which starts off Hwy 97 south of Oroville, WA, and ends on top of Mt Hull (4619'):

Dave Kofranek submitted this 8.5-mile off-trail loop (approx 2500' elevation gain):

This route loops Little Wildhorse Lake and Wildhorse Lake proper via their drainages.

This is the southernmost 20 miles of the Appalachian Trail, making a 40-mile out & back with 9000' of elevation gain.

The Wind River High Route is 97 miles long, 65 percent off-trail, and follows the alpine crest of Wyoming’s Wind River Range, usually hovering between 10,000 and 12,000 feet. Its termini are Bruce Bridge and Trail Lakes, both on the eastern side of the range, connected by long cross-country segments with short bits of trail.  Modelled after the design of the Sierra High Route, it stays as high as possible while traversing no technical terrain (Class 5), crosses mostly non-crevassed glaciers, and offers plenty of bo