Our main panel doesn't have any more openings to feed a 2nd subpanel that I like to install. I was thinking of using the 2" opening and clamp in the main breaker that is feeding the 1st subpanel for my wire to the 2nd subpanel. The 1st subpanel is 100A and its feed is a 2/3 romax. This 2/3 romex is about an inch in diameter and is carrying 2 HOTs, natural, and ground. Question: since there is room under the 2" clamp in the main breaker, can I use the same hole and clamp to feed a 3/3 romex for a 2nd subpanel?

I've noticed that in our main breaker with romex wires, any 240v breaker with big AMP ratings, such as dual-breaker 50A (oven), dual-breaker 40A (AC), dual-breaker 30A (Dryer), are all going through only one hole and clamp. And further obsevation, any romex on 120v breakers for 15A and 20A, have 2 romex wires per hole and clamp.

A General question on this topic: Would the 2 HOT wires be the limit of holes and clamps in the main panel (that would explain the way the holes and clamps are configured for the 120v and 240v circuits in my main panel)? And would the natural wire(s) be considered as carrying conductor for this holes and clamps determination?

You can only use one cable connector for multiple cables if the connector is rated to handle more than one cable.

I am sure the connector you have is not rated for more than one.

Are you saying there are no more knockouts to use, or absolutley no more room for another knockout?

I would think there is plenty of room to make another knockout for this new cable.

Holes (knockout) and connectors have no bearing on current carrying conductors, only that the cable is connected properly to the box.

Thanks tkrussell for a great answer.
The electrician that installed the main panel when the house was built, installed the
Main panel in a very VERY tight spot. As a result, it is often difficult to work on this panel.
All the left sides and bottom knockouts are against the outside wall supporting studs,
So they are not accessible at all. The top knockouts are all taken. There are knockouts
On the right side of the panel, however, there is only 2 inch space between the
Panel and the stud. Which makes feeding a romex copper 2/3 or 3/3 very difficult due
To the wire's resistance to form into tight spots. To complicate the issue even further,
There are one HOT and one natural 4/0 AL wire on the right side, tightly against the
Right side of the main panel where the knockouts are located.

Are you suggesting that I can drill a hole into the top of the panel to make my own
Knockout, if yes, what drill bit can I use to drill a 1.25 inch hole into heavy gauge panel?

Again due to the little space on the top of the panel and with all the
Wires there, if I were to drill a hole there (or better yet, drill a 1.25 inch hole
Where a 3/4" knockout is at and reroute it's wire to the right side of panel), I would
Need to remove some circuits to avoid damage to the top wires, and have to
Use 90 degree angle drill.

Actually, what you use is a conduit punch

Some info is here:

Tips on Punching the Right-Sized Hole, by John Bisset

You usually drill about a 3/8 diameter hole. Bullit bits or pilor point bits with drill stops (collars) prevent the drill from hitting bad places. In sheet metal, once you punch through the hole acts like threads and pulls the bit into the box sometimes with disastrous results

Automatic center punches make the initial depression so theta the bit will not wander. A brad point or pilot point bit with a collor can be used to drill the initial hole. Sometimes step drilling is necessary. A Unibit will drill a round hole in sheet metal, so that the bolt of the punch will pass through easily, otherwise you get a triangular looking hole

You then put the cutter on one side and the die on the other and put a bolt between them. You tighten the bolt until the die cuts through.

Electricians will have a hydraulic version of this tool. A unibit, drill bit, punch and automatic center punch could run you about $75.00

Reminder that there are right angle romex connectors and romex connectors that will support two #12 or #14 in the same knockout. They clamp each wire separately.

You can enlarge knockouts with the punch as you suggested. Large Unibits don't work as well, but they won't be pulled into the case.