To the Editor: Thank you for the opportunity to respond to the letter from ten Broeke and Nielsen1 regarding our review article “PMS2 Monoallelic Mutation Carriers: The Known Unknown.”2 We were delighted to see the publication of data from 98 mostly unpublished families with germ-line PMS2 mutations, including 2,548 family members with 377 proven carriers, by ten Broeke et al.3 while our review was in press. Their study greatly expands the number of known families with PMS2 mutations. As noted in our article, a major impediment to developing recommendations for these families has been the paucity of quality data. The article by ten Broeke and colleagues3 represents a significant step toward improving that situation.

On the basis of the data we had available, we concluded that initiation of colon surveillance at age 25 still seems reasonable for PMS2 mutation carriers because 8% of gene carriers in our series of 234 putative, monoallelic carriers developed colorectal cancer (CRC) before age 30. In the new cohort studied by ten Broeke et al., six of seven cases of CRC that developed before age 30 occurred in the index patient, again raising the specter of a possible undetected biallelic process or digenic process in some families. Accordingly, ten Broeke et al3 divided screening recommendations for first-degree relatives by index cases diagnosed before age 30 and index cases diagnosed after age 30. They recommend starting screening 2–5 years earlier than the age at diagnosis of the index family member for first-degree relatives of individuals with CRC before age 30 and initiating CRC screening at age 30 for all other PMS2 monoallelic mutation carriers.

Based on their data, this does not seem unreasonable, and such a recommendation would be consistent with an assumption that the very-early-onset cases are somehow different, perhaps because of a missed biallelic/digenic mutation. Still, whether early onset of CRC in some individuals is caused by an alternative mechanism or is simply part of the range experienced by monoallelic PMS2 mutation carriers is currently unknown. Unfortunately, until this issue can be fully resolved, the decision of whether to start colon screening at age 25 or 30 in PMS2 monoallelic mutation carriers will rely on patient and provider preferences, resources, and tolerance for risk, with no definite right or wrong approach.

Disclosure

The authors declare no conflict of interest.