Lynch syndrome (HNPCC) is associated with endometrial carcinoma. Which MMR gene mutation has the highest penetrance for endometrial carcinoma (highest lifetime risk ~60%) compared to colorectal cancer risk?
- A MLH1
- B MSH2
- C MSH6 ✓
- D PMS2
Correct answer: C. MSH6
Explanation
Among Lynch syndrome-associated MMR gene mutations, MSH6 mutations have the highest penetrance specifically for endometrial carcinoma (lifetime risk ~60–70%) and relatively lower penetrance for colorectal cancer compared to MLH1 and MSH2 mutations. MSH6 mutations are sometimes referred to as 'gynaecological Lynch syndrome' because endometrial cancer can be the sentinel Lynch-associated malignancy in MSH6 carriers. MLH1 and MSH2 mutations carry high risks for both colorectal and endometrial cancers. PMS2 mutations have the lowest penetrance for both sites.
Reference: Shaw's Textbook of Gynaecology, 17th ed.
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