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Genet Med. 2016 Jan;18(1):13-9. doi: 10.1038/gim.2015.27. Epub 2015 Apr 9.

PMS2 monoallelic mutation carriers: the known unknown.

Author information

1
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
2
Department of Medical Genetics, Mayo Clinic, Jacksonville, Florida, USA.
3
Department of Internal Medicine, Gastroenterology, Baylor Research Institute, Charles Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA.
4
Baylor College of Medicine, Houston, Texas, USA.
5
Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
6
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
7
Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
8
Genetic Epidemiology Research Institute, University of California, Irvine, Irvine, California, USA.
9
Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
10
The Royal Melbourne Hospital, Victoria, Australia.
11
Department of Preventive Medicine and Public Health, Creighton University, Omaha, Nebraska, USA.
12
Division of Clinical Cancer Genetics, City of Hope, Duarte, California, USA.
13
Division of Gastroenterology, Brigham and Women's Hospital and Population Sciences Division, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
14
Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
15
New Zealand Familial Gastrointestinal Cancer Registry, Auckland City Hospital, Auckland, New Zealand.
16
Zane Cohen Centre for Digestive Diseases, Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital, Toronto, Canada.
17
Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
18
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
19
Department of Medical Genetics, Mayo Clinic, Rochester, Minnesota, USA.
20
Division of Gastroenterology, University of California, San Francisco, School of Medicine, San Francisco, California, USA.
21
Department of Gynecologic Oncology and Reproductive Medicine, M.D. Anderson Cancer Center, Houston, Texas, USA.
22
Department of Health Sciences Research, Mayo Clinic, Scottsdale, Arizona, USA.

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.

PMID:
25856668
PMCID:
PMC4834863
DOI:
10.1038/gim.2015.27
[Indexed for MEDLINE]
Free PMC Article

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