how so? they could just do a "keep" for mass effect.

Because, as you say, the genophage is a pretty big deal. You can't reduce its consequences down to changes in a few dialogue options without trivializing it to a ridiculous degree and you can't make the differences as large as they should be or you're looking at making two completely separate games.

I'd actually be in favor of going forward with the franchise by making sequels take place after a "canonical" Shepard, but leaving the option open for sequels to different trilogy playthroughs. So one game would take place after the genophage cure was sabotaged, the quarians were killed and Shepard ASSUMED DIRECT CONTROL, but the team would leave the option open for future games to take place post-Destroy with a cured genophage and peace made between the geth and quarians. Use the trilogy as the basis for a bunch of diverging timelines.

But I strongly doubt that could be done well in a single game (and obviously, Bioware also thinks so or they would'n't have gone to Andromeda).