Classifying MMR Variants: Time for Revised Nomenclature in Lynch Syndrome

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2013 Mar 28

PMID 23532885

Citations 4

Authors

Y Nancy You

Eduardo Vilar

Affiliations

Soon will be listed here.

Abstract

Inactivating germline mutations in DNA mismatch repair (MMR) genes are diagnostic for Lynch syndrome. However, the clinical significance of missense variants is uncertain. A threshold level of compromised MLH1 expression, correlating with greater protein instability and MMR functional defect, has been identified to help classify the pathogenicity of missense variants.

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References

Hinrichsen I, Brieger A, Trojan J, Zeuzem S, Nilbert M, Plotz G . Expression defect size among unclassified MLH1 variants determines pathogenicity in Lynch syndrome diagnosis. Clin Cancer Res. 2013; 19(9):2432-41. DOI: 10.1158/1078-0432.CCR-12-3299. View

Borras E, Pineda M, Brieger A, Hinrichsen I, Gomez C, Navarro M . Comprehensive functional assessment of MLH1 variants of unknown significance. Hum Mutat. 2012; 33(11):1576-88. DOI: 10.1002/humu.22142. View

Plon S, Eccles D, Easton D, Foulkes W, Genuardi M, Greenblatt M . Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum Mutat. 2008; 29(11):1282-91. PMC: 3075918. DOI: 10.1002/humu.20880. View

Heald B, Plesec T, Liu X, Pai R, Patil D, Moline J . Implementation of universal microsatellite instability and immunohistochemistry screening for diagnosing lynch syndrome in a large academic medical center. J Clin Oncol. 2013; 31(10):1336-40. PMC: 4878100. DOI: 10.1200/JCO.2012.45.1674. View

Syngal S, Fox E, Li C, DOvidio M, Eng C, Kolodner R . Interpretation of genetic test results for hereditary nonpolyposis colorectal cancer: implications for clinical predisposition testing. JAMA. 1999; 282(3):247-53. DOI: 10.1001/jama.282.3.247. View

Rodriguez-Soler M, Perez-Carbonell L, Guarinos C, Zapater P, Castillejo A, Barbera V . Risk of cancer in cases of suspected lynch syndrome without germline mutation. Gastroenterology. 2013; 144(5):926-932.e1. DOI: 10.1053/j.gastro.2013.01.044. View

Lindor N, Rabe K, Petersen G, Haile R, Casey G, Baron J . Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA. 2005; 293(16):1979-85. PMC: 2933042. DOI: 10.1001/jama.293.16.1979. View

Thompson B, Goldgar D, Paterson C, Clendenning M, Walters R, Arnold S . A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the Colon Cancer Family Registry. Hum Mutat. 2012; 34(1):200-9. PMC: 3538359. DOI: 10.1002/humu.22213. View

Lynch H, Shaw M, Magnuson C, Larsen A, KRUSH A . Hereditary factors in cancer. Study of two large midwestern kindreds. Arch Intern Med. 1966; 117(2):206-12. View

10.

Spurdle A . Clinical relevance of rare germline sequence variants in cancer genes: evolution and application of classification models. Curr Opin Genet Dev. 2010; 20(3):315-23. DOI: 10.1016/j.gde.2010.03.009. View

11.

Colas C, Coulet F, Svrcek M, Collura A, Flejou J, Duval A . Lynch or not Lynch? Is that always a question?. Adv Cancer Res. 2012; 113:121-66. DOI: 10.1016/B978-0-12-394280-7.00004-X. View

12.

Vasen H, Mecklin J, Khan P, Lynch H . The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum. 1991; 34(5):424-5. DOI: 10.1007/BF02053699. View