Journal of Genetic Counseling

, Volume 21, Issue 4, pp 484–493 | Cite as

Identification of Individuals at Risk for Lynch Syndrome Using Targeted Evaluations and Genetic Testing: National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Colorectal Cancer Joint Practice Guideline

  • Scott M. Weissman
  • Randall Burt
  • James Church
  • Steve Erdman
  • Heather Hampel
  • Spring Holter
  • Kory Jasperson
  • Matt F. Kalady
  • Joy Larsen Haidle
  • Henry T. Lynch
  • Selvi Palaniappan
  • Paul E. Wise
  • Leigha Senter
Professional Issues


Identifying individuals who have Lynch syndrome (LS) involves a complex diagnostic work up that includes taking a detailed family history and a combination of various genetic and immunohistochemical tests. The National Society of Genetic Counselors (NSGC) and the Collaborative Group of the Americas on Inherited Colorectal Cancer (CGA-ICC) have come together to publish this clinical practice testing guideline for the evaluation of LS. The purpose of this practice guideline is to provide guidance and a testing algorithm for LS as well as recommendations on when to offer testing. This guideline does not replace a consultation with a genetics professional. This guideline includes explanations in support of this and a summary of background data. While this guideline is not intended to serve as a review of LS, it includes a discussion of background information on LS, and cites a number of key publications which should be reviewed for a more in-depth understanding of LS. These guidelines are intended for genetic counselors, geneticists, gastroenterologists, surgeons, medical oncologists, obstetricians and gynecologists, nurses and other healthcare providers who evaluate patients for LS.


Lynch syndrome Colorectal neoplasms Microsatellite instability Immunohistochemistry Practice guideline DNA mismatch repair Genetic testing Uterine neoplasms 



This practice guideline was developed by members of the NSGC and CGA-ICC to assist genetic counselors and other health care providers in making decisions about appropriate management of genetic concerns; including access to and/or delivery of services. This practice guideline focuses on a clinical or practice-based issue, and is the result of a review and analysis of current professional literature believed to be reliable. As such, information and recommendations within this joint NSGC and CGA-ICC practice guideline reflect scientific and clinical knowledge current as of the time of publication, is only current as of its publication date, and is subject to change without notice as advances emerge.

In addition, variations in practice, which take into account the needs of the individual patient and the resources and limitations unique to the institution or type of practice, may warrant approaches, treatments and/or procedures that differ from the recommendations outlined in this guideline. Therefore, these recommendations should not be construed as dictating an exclusive course of management, nor does the use of such recommendations guarantee a particular outcome. Genetic counseling practice guidelines are never intended to displace a health care provider’s best medical judgment based on the clinical circumstances of a particular patient or patient population. This practice guideline is published by NSGC and CGA-ICC for educational and informational purposes only, and neither NSGC nor CGA-ICC “approves” or “endorses” any specific methods, practices, or sources of information contained herein.


  1. Backes, F. J., Leon, M. E., Ivanov, I., Suarez, A., Frankel, W. L., Hampel, H., et al. (2009). Prospective evaluation of DNA mismatch repair protein expression in primary endometrial cancer. Gynaecological Oncology, 114, 486–490.CrossRefGoogle Scholar
  2. Baglietto, L., Lindor, N. M., Dowty, J. G., White, D. M., Wagner, A., Gomez Garcia, E. B., et al. (2009). Risks of Lynch syndrome cancers for MSH6 mutation carriers. Journal of the National Cancer Institute, 102(3), 193–201.PubMedCrossRefGoogle Scholar
  3. Bao, F., Panarelli, N. C., Rennert, H., Sherr, D. L., & Yantiss, R. K. (2010). Neoadjuvant therapy induces loss of MSH6 expression in colorectal carcinoma. The American Journal of Surgical Pathology, 34, 1798–1804.PubMedCrossRefGoogle Scholar
  4. Barrow, E., Alduaij, W., Robinson, L., Shenton, A., Clancy, T., Lalloo, F., et al. (2008). Colorectal cancer in HNPCC: cumulative lifetime incidence, survival and tumour distribution. A report of 121 families with proven mutations. Clinical Genetics, 74(3), 233–242.PubMedCrossRefGoogle Scholar
  5. Boland, C. R. (2005). Evolution of the nomenclature for the hereditary colorectal cancer syndromes. Familial Cancer, 4(3), 211–218.PubMedCrossRefGoogle Scholar
  6. Boland, C. R., Thibodeau, S. N., Hamilton, S. R., Sidransky, D., Eshleman, J. R., Burt, R. W., et al. (1998). A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Research, 58, 5248–5257.PubMedGoogle Scholar
  7. Capelle, L. G., Van Grieken, N. C., Lingsma, H. F., Steyerberg, E. W., Klokman, W. J., Bruno, M. J., et al. (2010). Risk and epidemiological time trends of gastric cancer in Lynch syndrome carriers in the Netherlands. Gastroenterology, 138, 487–492.PubMedCrossRefGoogle Scholar
  8. Chang, D. K., Metzgar, D., Willis, C., & Boland, C. R. (2001). Microsatellites in the eukaryotic DNA mismatch repair genes as modulators of evolutionary mutation rate. Genome Research, 11, 1145–1146.PubMedCrossRefGoogle Scholar
  9. Chao, E. C., Velasquez, J. L., Witherspoon, M. S., Rozek, L. S., Peel, D., Ng, P., et al. (2008). Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). Human Mutation, 29(6), 852–860.PubMedCrossRefGoogle Scholar
  10. Choi, M. Y., Lauwers, G. Y., Hur, C., Willett, C. G., & Chung, D. C. (2007). Microsatellite instability is frequently observed in rectal cancer and influenced by neoadjuvant chemoradiation. International Journal of Radiation Oncology, Biology, and Physics, 68(5), 1584.CrossRefGoogle Scholar
  11. Clendenning, M., Hampel, H., LaJeunesse, J., Lindblom, A., Lockman, J., Nilbert, M., et al. (2006). Long-range PCR facilitates the identification of PMS2-specific mutations. Human Mutation, 27, 490–495.PubMedCrossRefGoogle Scholar
  12. De Jong, A. E., van Puijenbroek, M., Hendriks, Y., Tops, C., Wijnen, J., Ausems, M. G., et al. (2004). Microsatellite instability, immunohistochemistry, and additional PMS2 staining in suspected hereditary nonpolyposis colorectal cancer. Clinical Cancer Research, 10(3), 972–980.PubMedCrossRefGoogle Scholar
  13. Evaluation of Genomic Applications in Practice and Prevention Working Group. (2009). Recommendations from the EGAPP working group: genetic testing strategies in the newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genetics in Medicine, 11(1), 35–41.CrossRefGoogle Scholar
  14. Garg, K., Leitao, M. M., Kauff, N. D., Hansen, J., Kosarin, K., Shia, J., et al. (2009). Selection of endometrial carcinomas for DNA mismatch repair protein immunohistochemistry using patient age and tumor morphology enhances detection of mismatch repair abnormalities. The American Journal of Surgical Pathology, 33, 925–933.PubMedCrossRefGoogle Scholar
  15. Hampel, H. (2010). Point: justification for Lynch syndrome screening among all patients with newly diagnosed colorectal cancer. Journal of the National Comprehensive Cancer Network, 8, 597–601.PubMedGoogle Scholar
  16. Hampel, H., Frankel, W. L., Martin, E., Arnold, M., Khanduja, K., Kuebler, P., et al. (2005a). Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). The New England Journal of Medicine, 352(18), 1851–1860.CrossRefGoogle Scholar
  17. Hampel, H., Stephens, J. A., Pukkala, E., Sankila, R., Aaltonen, L. A., Mecklin, J. P., et al. (2005b). Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset. Gastroenterology, 129(2), 415–421.Google Scholar
  18. Hampel, H., Frankel, W., Panescu, J., Lockman, J., Sotamaa, K., Fix, D., et al. (2006). Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among EC patients. Cancer Research, 66(15), 7810–7817.PubMedCrossRefGoogle Scholar
  19. Hampel, H., Panescu, J., Lockman, J., Sotamaa, K., Fix, D., Comeras, I., et al. (2007). Comment on: screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. Cancer Research, 67(19), 9603.PubMedCrossRefGoogle Scholar
  20. Hampel, H., Frankel, W. L., Martin, E., Arnold, M., Khanduja, K., Kuebler, P., et al. (2008). Feasibility of screening for Lynch syndrome among patients with colorectal cancer. Journal of Clinical Oncology, 26(35), 5783–5788.PubMedCrossRefGoogle Scholar
  21. Hitchins, M. P., & Ward, R. L. (2009). Constitutional (germline) MLH1 epimutation as an aetiological mechanism for hereditary non-polyposis colorectal cancer. Journal of Medical Genetics, 46(12), 793–802.PubMedCrossRefGoogle Scholar
  22. Hitchins, M. P., Rapkins, R. W., Kwok, C., Srivastava, S., Wong, J. J. L., Khachigian, L. M., et al. (2011). Dominantly inherited constitutional epigenetic silencing of MLH1 in a cancer-affected family is linked to a single nucleotide variant with the 5′UTR. Cancer Cell, 20, 200–213.PubMedCrossRefGoogle Scholar
  23. Jass, J. R. (2006). Hereditary non-polyposis colorectal cancer: the rise and fall of a confusing term. World Journal of Gastroenterology, 12(31), 4943–4950.PubMedGoogle Scholar
  24. Kuiper, R. P., Vissers, L. E. L. M., Venkatachalam, R., Bodmer, D., Hoenselaar, E., Goossens, M., et al. (2011). Recurrence and variability of germline EPCAM deletions in Lynch syndrome. Human Mutation, 32(4), 407–414.PubMedCrossRefGoogle Scholar
  25. Ladabaum, U., Wang, G., Terdiman, J., Blanco, A., Kuppermann, M., Boland, C. R., et al. (2011). Strategies to identify Lynch syndrome among patients with colorectal cancer: a cost effective analysis. Annals of Internal Medicine, 155(2), 69–79.PubMedGoogle Scholar
  26. Lightenberg, M. J., Kuiper, R. P., Chan, T. L., Goossens, M., Hebeda, K. M., Voorendt, M., et al. (2009). Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1. Nature Genetics, 41, 112–117.CrossRefGoogle Scholar
  27. Lindor, N. M. (2009). Familial colon cancer type X: the other half of hereditary non polyposis colorectal cancer syndrome. Surgical Oncology Clinics of North America, 18, 637–645.PubMedCrossRefGoogle Scholar
  28. Lindor, N. M., Burgart, L. J., Leontovich, O., Goldberg, R. M., Cunningham, J. M., Sargent, D., et al. (2002). Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. Journal of Clinical Oncology, 20, 1043–1048.PubMedCrossRefGoogle Scholar
  29. Lindor, N. M., Rabe, K., Petersen, G. M., Haile, R., Casey, G., Baron, J., et al. (2005). Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. Journal of the American Medical Association, 293(16), 1979–1985.PubMedCrossRefGoogle Scholar
  30. Lindor, N. M., Petersen, G. M., Hadley, D. W., Kinney, A. Y., Miesfeldt, S., Lu, K. H., et al. (2006). Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. Journal of the American Medical Association, 296(12), 1507–1517.PubMedCrossRefGoogle Scholar
  31. Loughrey, M. B., Waring, P. M., Tan, A., Trivett, M., Kovalenko, S., Beshay, V., et al. (2007). Incorporation of somatic BRAF mutation testing into an algorithm for the investigation of hereditary non-polyposis colorectal cancer. Familial Cancer, 6(3), 301–310.PubMedCrossRefGoogle Scholar
  32. Modica, I., Soslow, R. A., Black, D., Tornos, C., Kauff, N., & Shia, J. (2007). Utility of immunohistochemistry in predicting microsatellite instability in endometrial carcinoma. American Journal of Surgical Pathology, 31, 744–751.PubMedCrossRefGoogle Scholar
  33. Müller, A., Giuffre, G., Edmonston, T. B., Mathiak, M., Roggendorf, B., Heinmöller, E., et al. (2004). Challenges and pitfalls in HNPCC screening by microsatellite analysis and immunohistochemistry. Journal of Molecular Diagnostics, 6, 308–315.PubMedCrossRefGoogle Scholar
  34. Mvundura, M., Grosse, S. D., Hampel, H., & Palomaki, G. E. (2010). The cost-effectiveness of genetic testing strategies for Lynch syndrome among newly diagnosed patients with colorectal cancer. Genetics in Medicine, 12(2), 93–104.PubMedCrossRefGoogle Scholar
  35. Nakagawa, H., Lockman, J. C., Frankel, W. L., Hampel, H., Steenblock, K., Burgart, L. J., et al. (2004). Mismatch repair gene PMS2: disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation. Cancer Research, 64(14), 4721–4727.PubMedCrossRefGoogle Scholar
  36. Niessen, R. C., Kleibeuker, J. H., Westers, H., Jager, P. O., Rozeveld, D., Bos, K. K., et al. (2009a). PMS2 involvement in patients suspected of Lynch syndrome. Genes, Chromosomes & Cancer, 48(4), 322–329.CrossRefGoogle Scholar
  37. Niessen, R. C., Hofstra, R. M. W., Westers, H., Lightenberg, M. J. L., Kooi, K., Jager, P. O. J., et al. (2009b). Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome. Genes, Chromosomes & Cancer, 48, 737–744.CrossRefGoogle Scholar
  38. Palomaki, G. E., McClain, M. R., Melillo, S., Hampel, H., & Thibodeau, S. N. (2009). EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome. Genetics in Medicine, 11(1), 42–65.PubMedCrossRefGoogle Scholar
  39. Peltomaki, P., & Vasen, H. (2004). Mutations associated with HNPCC predisposition—Update of ICG-HNPCC/INSiGHT mutation database. Disease Markers, 20(4–5), 269–276.PubMedGoogle Scholar
  40. Plaschke, J., Engel, C., Kruger, S., Holinski-Feder, E., Pagenstecher, C., Mangold, E., et al. (2004). Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium. Journal of Clinical Oncology, 22(22), 4486–4494.PubMedCrossRefGoogle Scholar
  41. Rijcken, F. E., Hollema, H., & Kleibeuker, J. H. (2002). Proximal adenomas in hereditary non-polyposis colorectal cancer are prone to rapid malignant transformation. Gut, 50, 382–386.PubMedCrossRefGoogle Scholar
  42. Senter, L., Clendenning, M., Sotamaa, K., Hampel, H., Green, J., Potter, J. D., et al. (2008). The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology, 135(2), 419–428.PubMedCrossRefGoogle Scholar
  43. Shia, J., Tang, L. H., Vakiani, E., Guillem, J. G., Stadler, Z. K., Soslow, R. A., et al. (2009). Immunohistochemistry as first-line screening for detecting colorectal cancer patients at risk for hereditary non-polyposis colorectal cancer syndrome: a 2-antibody panel may be as predictive as a 4-antibody panel. American Journal of Surgical Pathology, 33, 1639–1645.PubMedCrossRefGoogle Scholar
  44. Simpkins, S. B., Bocker, T., Swisher, E. M., Mutch, D. G., Gersell, D. J., Kovatich, A. J., et al. (1999). MLH1 promoter methylation and gene silencing is the primary cause of microsatellite instability in sporadic endometrial cancers. Human Molecular Genetics, 8(4), 661–666.PubMedCrossRefGoogle Scholar
  45. Stoffel, E., Mukherjee, B., Raymond, V. M., Tayob, N., Kastrinos, F., Sparr, J., et al. (2009). Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome. Gastroenterology, 137(5), 1621–1627.PubMedCrossRefGoogle Scholar
  46. The NCCN Clinical Practice Guidelines in Oncology™ Colorectal Cancer Screening Version 2.2011 (2011) National Comprehensive Cancer Network, Inc. Retrieved from
  47. Umar, A., Boland, C. R., Terdiman, J. P., Syngal, S., de la Chapelle, A., Ruschoff, J., et al. (2004). Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. Journal of the National Cancer Institute, 96(4), 261–268.PubMedCrossRefGoogle Scholar
  48. Vasen, H. F., Mecklin, J. P., Khan, P. M., & Lynch, H. T. (1991). The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Diseases of the Colon & Rectum, 34(5), 424–425.CrossRefGoogle Scholar
  49. Vasen, H. F., Mecklin, J. P., Khan, P. M., & Lynch, H. T. (1994). The International Collaborative Group on HNPCC. Anticancer Research, 14, 1661–1664.PubMedGoogle Scholar
  50. Vasen, H. F., Watson, P., Mecklin, J. P., & Lynch, H. T. (1999). New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology, 116(6), 1453–1456.PubMedCrossRefGoogle Scholar
  51. Vaughn, C. P., Robles, J., Swensen, J. J., Miller, C. E., Lyon, E., Mao, R., et al. (2010). Clinical analysis of PMS2: mutation detection and avoidance of pseudogenes. Human Mutation, 31, 588–593.PubMedGoogle Scholar
  52. Wang, L., Cunningham, J. M., Winters, J. L., Guenther, J. C., French, A. J., Boardman, L. A., et al. (2003). BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair. Cancer Research, 63(17), 5209–5212.PubMedGoogle Scholar
  53. Watson, P., Vasen, H. F., Mecklin, J. P., Bernstein, I., Aarnio, M., Järvinen, H. J., et al. (2008). The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. International Journal of Cancer, 123, 444–449.CrossRefGoogle Scholar
  54. Weissman, S. M., Bellcross, C., Chimera Bittner, C., Freivogel, M. E., Larsen Haidle, J., Kaurah, P., et al. (2011). Genetic counseling considerations in the evaluation of families with Lynch syndrome—a review. Journal of Genetic Counseling, 20(1), 5–19.PubMedCrossRefGoogle Scholar
  55. Wimmer, K., & Etzler, J. (2008). Constitutional mismatch repair deficiency syndrome: have we so far seen only the tip of the iceberg? Human Genetics, 2008(124), 105–122.CrossRefGoogle Scholar
  56. Zighelboim, I., Powell, M., Babb, S., Whelan, A., Schmidt, A., Clendenning, M., et al. (2009). Epitope-positive truncating MLH1 mutation and loss of PMS2: implications for IHC-directed genetic testing for lynch syndrome. FamCancer, 8(4), 501–504.Google Scholar

Copyright information

© National Society of Genetic Counselors, Inc. 2011

Authors and Affiliations

  • Scott M. Weissman
    • 1
  • Randall Burt
    • 2
  • James Church
    • 3
  • Steve Erdman
    • 4
    • 5
  • Heather Hampel
    • 6
  • Spring Holter
    • 7
  • Kory Jasperson
    • 2
  • Matt F. Kalady
    • 3
  • Joy Larsen Haidle
    • 8
  • Henry T. Lynch
    • 9
  • Selvi Palaniappan
    • 10
  • Paul E. Wise
    • 11
  • Leigha Senter
    • 6
  1. 1.Center for Medical GeneticsNorthShore University HealthSystemEvanstonUSA
  2. 2.Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUSA
  3. 3.Digestive Disease Institute, Cleveland Clinic FoundationClevelandUSA
  4. 4.Nationwide Children’s HospitalColumbusUSA
  5. 5.The Ohio State UniversityColumbusUSA
  6. 6.Arthur G. James Cancer Hospital and Richard J. Solove Research InstituteThe Ohio State University Comprehensive Cancer CenterColumbusUSA
  7. 7.Zane Cohen Centre for Digestive Diseases Clinical Research CentereMount Sinai HospitalTorontoCanada
  8. 8.Hubert H. Humphrey Cancer Center, North Memorial HealthcareRobbinsdaleUSA
  9. 9.Department of Preventative MedicineCreighton Hereditary Cancer CenterOmahaUSA
  10. 10.Hereditary Cancer ProgramNorthside HospitalAtlantaUSA
  11. 11.Vanderbilt Hereditary Colorectal Cancer RegistryVanderbilt University Medical CenterNashvilleUSA

Personalised recommendations