title: PMS2 monoallelic mutation carriers: the known unknown.
abstract: 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 Published reports of PMS2 germ-line mutations were combined with unpublished cases from the authors' research registries and clinical practices, and a discussion of potential modification of cancer screening guidelines was pursued.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.Genet Med 18 1, 13-19.
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
authors: McKinsey L
authors: ML
authors: Goodenberger
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
authors: Brittany C
authors: http://orcid.org/0000-0003-2870-1522
authors: BC
authors: Thomas
authors: Department of Medical Genetics, Mayo Clinic, Jacksonville, Florida, USA.
authors: Douglas
authors: D
authors: Riegert-Johnson
authors: Department of Internal Medicine, Gastroenterology, Baylor Research Institute, Charles Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA.
authors: C Richard
authors: CR
authors: Boland
authors: Baylor College of Medicine, Houston, Texas, USA.
authors: Sharon E
authors: SE
authors: Plon
authors: Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
authors: Mark
authors: M
authors: Clendenning
authors: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
authors: Aung Ko
authors: AK
authors: Win
authors: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
authors: Leigha
authors: L
authors: Senter
authors: Genetic Epidemiology Research Institute, University of California, Irvine, Irvine, California, USA.
authors: Steven M
authors: SM
authors: Lipkin
authors: Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors: Zsofia K
authors: ZK
authors: Stadler
authors: The Royal Melbourne Hospital, Victoria, Australia.
authors: Finlay A
authors: FA
authors: Macrae
authors: Department of Preventive Medicine and Public Health, Creighton University, Omaha, Nebraska, USA.
authors: Henry T
authors: HT
authors: Lynch
authors: Division of Clinical Cancer Genetics, City of Hope, Duarte, California, USA.
authors: Jeffrey N
authors: JN
authors: Weitzel
authors: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
authors: Albert
authors: A
authors: de la Chapelle
authors: Division of Gastroenterology, Brigham and Women's Hospital and Population Sciences Division, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors: Sapna
authors: S
authors: Syngal
authors: Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
authors: Patrick
authors: P
authors: Lynch
authors: New Zealand Familial Gastrointestinal Cancer Registry, Auckland City Hospital, Auckland, New Zealand.
authors: Susan
authors: S
authors: Parry
authors: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
authors: Mark A
authors: MA
authors: Jenkins
authors: Zane Cohen Centre for Digestive Diseases, Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital, Toronto, Canada.
authors: Steven
authors: S
authors: Gallinger
authors: Zane Cohen Centre for Digestive Diseases, Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital, Toronto, Canada.
authors: Spring
authors: S
authors: Holter
authors: Zane Cohen Centre for Digestive Diseases, Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital, Toronto, Canada.
authors: Melyssa
authors: M
authors: Aronson
authors: Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors: Polly A
authors: http://orcid.org/0000-0001-8786-0043
authors: PA
authors: Newcomb
authors: Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
authors: Terrilea
authors: T
authors: Burnett
authors: Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
authors: Loïc
authors: L
authors: Le Marchand
authors: Department of Medical Genetics, Mayo Clinic, Rochester, Minnesota, USA.
authors: Pavel
authors: P
authors: Pichurin
authors: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
authors: Heather
authors: H
authors: Hampel
authors: Division of Gastroenterology, University of California, San Francisco, School of Medicine, San Francisco, California, USA.
authors: Jonathan P
authors: JP
authors: Terdiman
authors: Department of Gynecologic Oncology and Reproductive Medicine, M.D. Anderson Cancer Center, Houston, Texas, USA.
authors: Karen H
authors: KH
authors: Lu
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
authors: Stephen
authors: S
authors: Thibodeau
authors: Department of Health Sciences Research, Mayo Clinic, Scottsdale, Arizona, USA.
authors: Noralane M
authors: NM
authors: Lindor
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D055088:Early Detection of Cancer / Q000379:methods; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D000070976:Mismatch Repair Endonuclease PMS2; D019683:Penetrance
chemical_list: D004268:DNA-Binding Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D045643:DNA Repair Enzymes