PMS2 monoallelic mutation carriers: The known unknown

McKinsey L. Goodenberger, Brittany C. Thomas, Douglas Riegert-Johnson, C. Richard Boland, Sharon E. Plon, Mark Clendenning, Aung Ko Win, Leigha Senter, Steven M. Lipkin, Zsofia K. Stadler, Finlay A. Macrae, Henry T. Lynch, Jeffrey N. Weitzel, Albert De La Chapelle, Sapna Syngal, Patrick Lynch, Susan Parry, Mark A. Jenkins, Steven Gallinger, Spring HolterMelyssa Aronson, Polly A. Newcomb, Terrilea Burnett, Loïc Le Marchand, Pavel Pichurin, Heather Hampel, Jonathan P. Terdiman, Karen H. Lu, Stephen Thibodeau, Noralane M. Lindor

Research output: Contribution to journalReview articlepeer-review

35 Scopus citations


Germ-line mutations in MLH1, MSH2, MSH6, and PMS2 have been shown to cause Lynch syndrome. The penetrance of the cancer and tumor spectrum has been repeatedly studied, and multiple professional societies have proposed clinical management guidelines for affected individuals. Several studies have demonstrated a reduced penetrance for monoallelic carriers of PMS2 mutations compared with the other mismatch repair (MMR) genes, but clinical management guidelines have largely proposed the same screening recommendations for all MMR gene carriers. The authors considered whether enough evidence existed to propose new screening guidelines specific to PMS2 mutation carriers with regard to age at onset and frequency of colonic screening. Published reports of PMS2 germ-line mutations were combined with unpublished cases from the authors' research registries and clinical practices, and a discussion of potential modification of cancer screening guidelines was pursued. A total of 234 monoallelic PMS2 mutation carriers from 170 families were included. Approximately 8% of those with colorectal cancer (CRC) were diagnosed before age 30, and each of these tumors presented on the left side of the colon. As it is currently unknown what causes the early onset of CRC in some families with monoallelic PMS2 germline mutations, the authors recommend against reducing cancer surveillance guidelines in families found having monoallelic PMS2 mutations in spite of the reduced penetrance.

Original languageEnglish (US)
Pages (from-to)13-19
Number of pages7
JournalGenetics in Medicine
Issue number1
StatePublished - Jan 1 2016


  • Lynch screening
  • Lynch syndrome
  • PMS2
  • PMS2 monoallelic
  • mismatch repair

ASJC Scopus subject areas

  • Genetics(clinical)


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