I've been thinking of homebrewing a system for this series myself, and have put a little thought into where focus should lie. Since you're asking, I'm telling
Note: I'm reading the books through audio book, if things are not spelled correctly, it's because I've never seen the words!
Setting wise, I think you should provide two. During and after Lord Rulers reign. I personally like during for reasons I'll detail below.
I'm a fan of smaller scale games, I've always been into the more selfish type of game like Shadowrun, do your shit, get your boxings and start a new run. I thought in particular that players would be part of Thieving Crews, Personal allomancers of nobility, or possibly a strike force commanded by the Lord Ruler himself. Players could also be brave members of the Rebellion, or independant rebellious troublemakers. I just believe that during Lord Rulers reign is a more diverse and interesting setting for role-playing.
I'm not a fan of
I hate class based systems and point buy or some such thing would be the way to go. Pushers and Pullers would have higher costs to increase their skill levels, while Smokers, Soothers and Tineyes would cost less. Combat oriented characters would in effect have less points for skills and other attributes, while the others while less useful in combat would be more useful outside of combat. I think this would give everyone their own time to shine in whatever situations arise.
Faruchemy I think should be an NPC thing. I can't think of any way to balance it properly and remain true to the source material. Though I'm not expert in game design, I just feel that as written it effectively has no draw backs unless under a time limit. Rarely do GMs enforce strict time limits, or pressures of such nature. Another issue would be the increased book keeping, I think. If I burn my stores for the strength of 10men for a turn, then next turn the strength of two men and finally the strength of 7 men, how many more turns until I'm out of juice?
Allomancy and the burning of metals, I'd assume it would just be assumed you had enough to do what needed to be done, with a few exceptions like Atium. No need to get bogged down in minor details of flairing and what burns at what rate. Especially since I've heard you're going for a less rules heavy system.
Mistborn is a touchy subject, who wouldn't want to play one? They're all powerful, have no real drawbacks and completely rule. Personally I'd include them in the game, but put a big red warning with it. It's all or nothing, everyone should be, or no one should be. It's upsetting to be useless in all situations when the guy beside you can do it just as well. Possibly rules wise they'd be weaker in all areas compared to their dedicated brothers, but then why would you pick one if you didn't have anything to really add in most situations other than a support role?
Combat should be deadly. If you don't burn Pewter you don't have much business not wearing armour and being careful. The brutality of combat is a large theme in the books I feel. Broken bones, smashed faces, near instant death mentioned in every fight. I'm not sure if I'd give PCs more skill or use mooks to make sure the average soldier does not kill them all willy nilly. This again is a very me thing, I know deadly combat isn't everyones cup of tea, but I'm just tossing it out there. Games where you could lose your character in any combat is more likely to make combat a distant option instead of the go to one. It incourages more role-playing when you fear someones honour guard can take you down. The other option is using mooks. Non imporant combatants that just die when you hit them once. Robin D. Laws made good use of them in Feng Shui.
It's late here, and I'm quite tired, I'm sure there are more points I'd like to hit, but now is not the time.
Fake edit: I use, a lot of these, comma thingies, when I am tired.