The key to answering this question is awareness of the facts that (i) the MSH2 protein is an essential partner in both of the MSH heterodimers (MSH2/MSH3 and MSH2/MSH6) that function in mismatch repair in mammalian cells, and (ii) the MLH1 protein is an essential partner in all three of the MLH heterodimers (MLH1/PMS1, MLH1/PMS2, and MLH1/MLH3). Consequently, a loss-of-function mutation in MSH2 would render both MSH heterodimers non-functional, and a loss-of-function mutation in MLH1 would render all three MLH heterodimers non-functional. Mutations in any of the other MSH or MLH genes would knock out only one of the relevant heterodimers, which would have much less effect and would be insufficient to cause HNPCC.
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