A prefix is a letter or a group of letters that ………. at the beginning of a word.
I would use "come" because of the preceding noun, which is "letter". However, I am not sure whether "comes" is ungrammatical here.
I think here the verb should agree with the nearer subject, which is 'a group of letters', and automatically I would use: 'comes'.
As you know 'group' could take a singular or a plural verb. Here you don't refer to each letter of the prefix individually, but you see them as one unit.
BTW, the definition of 'prefix' on 'LDOCE' is: A group of letters that is added to ...
DOC V has talked about using 'or' in one of his threads, but, unfortunately, I don't know which one.