After the Andromeda fiasco, many fans crave a return to the established lore of the Mass Effect trilogy. It's already rich with many branching possibilities for stories outside of Shepard's. A major event and potential catalyst for the series as a whole is the First Contact War, which would make a perfect prequel title. The First Contact War wasn't just a war between Turians and Humans. it was how humans discovered there was more to the universe and became part of Council Space.
The war began after humanity discovered Prothean artifacts and Mass Relays within their solar system. It caused technology to jump forward significantly and they used it to discover and colonize new planets and areas of the universe -- eventually coming into Council Space. Council Space is controlled by the Council on the Citadel and falls under its laws. After the Rachni Wars and everything that happened with the Krogan, they made a law banning the activation of new unknown relays to prevent any more incidents. Unfortunately, a relay humans tried to reactivate -- Relay 314 -- was in Council Space. Turians happened to be patrolling the area at the time and their ships opened fire on the unknown species, wanting to prevent another Rachni incident.
Only one human ship managed to escape and made it to the nearby colony, Shanxi, with the Turians in pursuit. The Turians easily took it over and bunkered there as the humans still on the colony tried to survive using guerrilla tactics. Full-on war nearly broke out between the species.
Luckily, the incident had drawn the attention of the Council, who negotiated peace. The Turians also had to pay reparations for firing first. This came to be known as the First Contact War to humanity and the Relay 314 Incident to the Turians.
This conflict essentially led to humanity becoming part of the Citadel and Council Space. It also established a background and lore for interactions with other species.
At the time, some Batarians were also aware of humans, because some human colonies had set up on what they claimed to be Batarian worlds during their travels. It made some sour towards humans, which is reflected in Mass Effect 2 when Shepard traverses the terminus systems. This all sets the stage for Shepard’s story and would make a great prequel for a new game.
A prequel could provide a glimpse into humanity's early space exploration, going to new worlds with no knowledge of species or etiquette on older ships and with older technology.
This period was also when human biotics were first discovered in children. This could make for an amazing side story with its own missions. There are politics in the games and even humans in the trilogy, years after all this, that still fear the unknown and can be bigoted towards other species and opinions. It would be a good entry for the codex to see how different factions reacted to the incident that led to biotic discovery.
The main story should focus on the events leading up to the First Contact War and humanity joining Council Space. Mass Effect 3 DLC Citadel hints at shadier parts of the war, but a more in-depth exploration of things that weren't recorded in the history books would be fantastic.
Since each Mass Effect title follows a specific protagonist, a First Contact War prequel could follow characters with major ties to ones players already know. For example, Ashley's grandfather, General Williams, who was the one to surrender Shanxi during the Turian attack. It triggered a series of prejudice in her family's military history and even humans were sour about it. Other ties to major characters would definitely come up in a prequel game.
There are plenty of threads to base a new Mass Effect game on, but the trilogy and Andromeda, established humanity's angle more than others. It makes the most sense for a prequel game to be about the First Contact War and its important role in the universe's history. Without it, Shepard's role may never have been established and the first human Spectre may not have happened or been as important.