In Lynch syndrome or Microsatellite Instability (MSI) syndrome, which proteins are evaluated for stability?

• A. MLH1 & PMS2
• B. MSH2 & MSH6
• C. MLH1, MSH2, & MSH6
• D. MLH1, MSH2, MSH6, & PMS2

Answer: (D)

The main idea is that Lynch syndrome is identified by evaluating the stability of the DNA mismatch repair (MMR) proteins in tumor tissue. These proteins—MLH1, PMS2, MSH2, and MSH6—work as two pairs (MLH1-PMS2 and MSH2-MSH6) to correct DNA mismatches. If one gene is defective or silenced, its partner can also be destabilized, leading to loss of protein expression detectable by testing. Because defects can occur in any of these genes, the standard assessment includes all four proteins to pinpoint which gene is affected and to guide further genetic testing. In practice, patterns of loss help distinguish which gene is likely mutated: for example, loss of MLH1 and its partner PMS2 suggests an MLH1 issue, while isolated loss of PMS2 points to a PMS2 defect, and similarly for MSH2 and MSH6. Testing only a subset could miss other defects, so evaluating all four provides the most comprehensive assessment.