Actually that IS the most common mistake. Submitting the manuscript when we ask to see a query letter only. The first thing we want to know is if you have a good idea. Sending the whole manuscript doesn't tell us that.
But I think maybe you meant what is the most common reason a good story may be turned down? Usually, it's because the ms. is too long for cost-effective paper publication. E-books can be any length, but anything over 100,000 words will eat most publishers alive with paper costs. The moment we read a query letter that begins:
My 140,000 word novel about sex, drugs, and rock & roll is the first of a series of 3 volumes of equal length....
The moment we hit 140,000 words, the word "NO!" pops right into our minds.
The other thing people don't do is count space, not words. A one-word line takes as much space to be printed as a 10 word line. Here's how editors and typesetters count words:
The first thing any editor needs to know is whether your story will fit in his space (or within his paper budget). If it won’t fit, he won’t buy it, no matter how good it is. Let me explain how typesetters count words, which is very different from the way spellcheck does. A line is 60 spaces long. Six spaces equals 1 word, or 10 words per line. If you have (as most people do) 25 lines per page, that gives you 250 words per double-spaced manuscript page. Now the following dialogue,
counts as 70 words, though only 8 are used. This way of calculating space, rather than words, is used throughout the industry and is the reason it drives editors absolutely crazy if you justify the right hand margin of your manuscript, or use a scalable font. It looks pretty, but the computer throws in lots of little half-spaces, or moves letters close together, and it throws off all the space calculations.