Advice on itinerary in October

So, would you be renting the car in Venice and driving to Tuscany/Umbria? If so, en route you could either start by following the coast and stop in Ravenna (or even San Marino, if you want to be able to say you've been there) -- or take the inland route with a stop in Ferrara and/or Bologna.

I don't think 5-6 nights is too mich for Tuscany & Umbria, but then I'd probably be delighted to spend 5-6 months there! My feeling is you can't go too far wrong with any of the towns & villages. However, for my taste a day trip into Florence would be woefully inadequate. Florence has a lot to see, and it's a gorgeous city in which to just walk around. If you really don't want to spend 2 nights in Florence, then consider 2 nights in Fiesole, making it quick & easy to "commute" into Florence each day.

You've allowed 4 nights for Rome, which I'd say is a bare minimum unless you really are not interested in cities.

It looks good to me, except maybe not enough for Florence. A couple of days in Florence, then off to the Tuscan/Umbrian countryside might be better if you can add a couple of days.

5-6 days in Tuscany/Umbria is not too much, not at all. We stayed near San Gimignano and visited many places. We did a one day trip to Florence as we had been there a couple of times before. We caught the train at Poggibonsi and it was an easy day for us. You can also easily get to Siena.

We have stayed in Umbria too and really like places there like Spoleto, Assisi, Todi, Montefalco, and Orvieto. If you pick a place centrally located you can do both Tuscany and Umbria but you will run out of time quickly.

When renting a villa in Tuscany/Umbria you almost always have to sign up for a week. So, you are probably looking at hotels or agritourismo's that let you stay by the day. That will make your trip easier. You can drop the car in Rome as well. That might make it easier too, since you could simply continue on rather than grabbing a long train ride.

The Bernina Express is a wonderful experience. We loved it!

I strongly encourage you to spend at least 3 nights in Venice. Two in Varenna is barely adequate, but two in Venice is barely enough.

From there I would spend 3 nights in Florence, without a car, then rent a car and go to southern Tuscany, perhaps staying near Montepulciano or Montalcino for 3 nights. You can not see a lot of Tuscany from one base, but combining a stay in Florence with a nice drive to the Val D'Orcia, then a couple of days to discover the area from Montalcino to Pienza to Montepulciano, you'll have a varied experience that will give you a flavor of Tuscany. Your last day you can drive to Orvieto, drop the car, have lunch in Orvieto and walk around, then take your train to Rome.

There is a very nice agriturismo near Montepulciano, Poggio-Etrusco. Pamela and Johnny are Americans who farm there. I am pretty sure you can rent for as few as three nights.

I would echo the comments of the others and encourage you to give some time to Florence, unless you don't much like cities and/or Renaissance art. And more time in Venice; remember that two nights equals only one full day.
Before you commit to Varenna, see what will be open at that time of year, and what the weather is generally like. One thing about cities if it's raining, there's always plenty to do indoors. Not so much the case with a place like Varenna, which may be beautiful, but not much going on if it's raining.

Thanks for all the feedback. I will rethink Florence and perhaps add some nights there. Perhaps staying in Varenna is not the best idea. It just liked so intriguing and picturesque.

Any thoughts where to stay in Venice and Rome

Venice and Rome. Well, in Venice, everything is close. I like the Dorsoduro. In Rome nothing is ideal because sights are spread out. I like being near a metro station.

We have found villa rentals through VRBO (Vacation Rental by Owner) to be wonderful. Most owners require a 3 night stay. Prices are reasonable according to your tastes.

You're going to have to face up to the fact that you can't see everything, even within the areas you've chosen. Italy is so rich in tourist attractions that in 16 trips we haven't seen all that we would like to see. In general, it's better to choose fewer destinations and explore them in greater depth than to skim lightly over more, simply because moving around eats up time.

For the Tuscany/Umbria section of your trip, 5 - 6 days is not too much, especially if you do a day in Florence. We once spent two weeks there and didn't run out of places to go. I suggest you choose accommodations near the A1. Look near the town of Chiusi. Don't forget to check out how long it takes to get to an entrance. Distances on a map can be deceptive due to narrow, winding roads. From that area we were able to do day trips to Perugia, Montepulciano, Montefalco, Arezzo, Cortona, Montalcino, Gubbio, Orvieto, and Pienza, Spello, and Bevagna.

In Venice, I like locations that are relatively close to Piazza San Marco, but out of the middle of the tourist fray. That means the close-in parts of Castello or Canneregio. The last couple of trips, we've stayed near Campo Santa Maria Formosa. I like the cafes on the campo, and the locals who gather where their kids' can kick around a soccer ball, but it's still close to San Marco.

In Rome, I like the area near Piazza Navona. It's centrally located, has lots of cafes with good people-watching. In Rome, because the metro doesn't go under the central, pedestrian part of the (ancient) city, it isn't as great of an option for getting around as in some cities, such as London or Paris.