Genetic Testing for Inherited Colorectal Cancer and Polyposis, 2021 Revision: a Technical Standard of the American College of Medical Genetics and Genomics (ACMG)

Overview

Journal Genet Med

Publisher Elsevier

Specialty Genetics

Date 2021 Jun 18

PMID 34140662

Citations 18

Authors

Rong Mao

Patti Krautscheid

Rondell P Graham

Arupa Ganguly

Suma Shankar

Matthew Ferber

Madhuri Hegde

Affiliations

Soon will be listed here.

Abstract

Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and 30% of all cases of CRC are believed to have a familial component and up to one-third of these (10%) are hereditary. Pathogenic germline variants in multiple genes have been associated with predisposition to hereditary CRC or polyposis. Lynch syndrome (LS) is the most common hereditary CRC syndrome, caused by variants in the mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 and is inherited in a dominant manner. Heritable conditions associated with colonic polyposis include familial adenomatous polyposis (FAP) associated with APC pathogenic variants, MUTYH-associated polyposis (MAP) caused by biallelic MUTYH pathogenic variants, and polymerase proofreading-associated polyposis (PPAP) caused by POLE or POLD1 pathogenic variants. Given the overlapping phenotypes of the cancer syndromes along with the limited sensitivity of using clinical criteria alone, a multigene panel testing approach to diagnose these conditions using next-generation sequencing (NGS) is effective and efficient. This technical standard is not recommended for use in the clinic for patient evaluation. Please refer to National Comprehensive Cancer Network (NCCN) clinical practice guidelines to determine an appropriate testing strategy and guide medical screening and management. This 2021 edition of the American College of Medical Genetics and Genomics (ACMG) technical standard supersedes the 2013 edition on this topic.

Citing Articles

Uncovering the genetic variation spectrum of colorectal polyposis from a multicentre cohort in China.

Yang M, Zhang D, Yuan Z, Chen D, Ju H, Wu B NPJ Precis Oncol. 2025; 9(1):75.

PMID: 40089605 DOI: 10.1038/s41698-025-00864-2.

Effect of genetic profiling on surgical decisions at hereditary colorectal cancer syndromes.

Goudarzi Y, Monirvaghefi K, Aghaei S, Amiri S, Rezaei M, Dehghanitafti A Heliyon. 2024; 10(15):e34375.

PMID: 39145015 PMC: 11320152. DOI: 10.1016/j.heliyon.2024.e34375.

Revolutionizing Gastrointestinal Disorder Management: Cutting-Edge Advances and Future Prospects.

Suri C, Pande B, Sahu T, Suhasini Sahithi L, Verma H J Clin Med. 2024; 13(13).

PMID: 38999541 PMC: 11242723. DOI: 10.3390/jcm13133977.

Detecting colorectal cancer using genetic and epigenetic biomarkers: screening and diagnosis.

Rezkitha Y, Panenggak N, Lusida M, Rianda R, Mahmudah I, Pradana A J Med Life. 2024; 17(1):4-14.

PMID: 38737656 PMC: 11080499. DOI: 10.25122/jml-2023-0269.

Chemoprophylaxis of precancerous lesions in patients who are at a high risk of developing colorectal cancer (Review).

Ogurchenok N, Khalin K, Bryukhovetskiy I Med Int (Lond). 2024; 4(3):25.

PMID: 38628384 PMC: 11019464. DOI: 10.3892/mi.2024.149.

References

Pearlman R, Frankel W, Swanson B, Zhao W, Yilmaz A, Miller K . Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. JAMA Oncol. 2016; 3(4):464-471. PMC: 5564179. DOI: 10.1001/jamaoncol.2016.5194. View

Seifert B, McGlaughon J, Jackson S, Ritter D, Roberts M, Schmidt R . Determining the clinical validity of hereditary colorectal cancer and polyposis susceptibility genes using the Clinical Genome Resource Clinical Validity Framework. Genet Med. 2018; 21(7):1507-1516. PMC: 6579719. DOI: 10.1038/s41436-018-0373-1. View

Goodenberger M, Lindor N . Lynch syndrome and MYH-associated polyposis: review and testing strategy. J Clin Gastroenterol. 2011; 45(6):488-500. DOI: 10.1097/MCG.0b013e318206489c. View

Markowitz S, Bertagnolli M . Molecular origins of cancer: Molecular basis of colorectal cancer. N Engl J Med. 2009; 361(25):2449-60. PMC: 2843693. DOI: 10.1056/NEJMra0804588. View

Vasen H . Review article: The Lynch syndrome (hereditary nonpolyposis colorectal cancer). Aliment Pharmacol Ther. 2008; 26 Suppl 2:113-26. DOI: 10.1111/j.1365-2036.2007.03479.x. View

Umar A, Boland C, Terdiman J, Syngal S, de la Chapelle A, Ruschoff J . Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004; 96(4):261-8. PMC: 2933058. DOI: 10.1093/jnci/djh034. View

Umar A, Risinger J, Hawk E, Barrett J . Testing guidelines for hereditary non-polyposis colorectal cancer. Nat Rev Cancer. 2004; 4(2):153-8. DOI: 10.1038/nrc1278. View

Win A, Jenkins M, Buchanan D, Clendenning M, Young J, Giles G . Determining the frequency of de novo germline mutations in DNA mismatch repair genes. J Med Genet. 2011; 48(8):530-4. PMC: 3436601. DOI: 10.1136/jmedgenet-2011-100082. View

Felton K, Gilchrist D, Andrew S . Constitutive deficiency in DNA mismatch repair: is it time for Lynch III?. Clin Genet. 2007; 71(6):499-500. DOI: 10.1111/j.1399-0004.2007.00801.x. View

10.

Felton K, Gilchrist D, Andrew S . Constitutive deficiency in DNA mismatch repair. Clin Genet. 2007; 71(6):483-98. DOI: 10.1111/j.1399-0004.2007.00803.x. View

11.

Hegde M, Chong B, Blazo M, Chin L, Ward P, Chintagumpala M . A homozygous mutation in MSH6 causes Turcot syndrome. Clin Cancer Res. 2005; 11(13):4689-93. DOI: 10.1158/1078-0432.CCR-04-2025. View

12.

Hayward B, De Vos M, Sheridan E, Bonthron D . PMS2 mutations in HNPCC. Clin Genet. 2004; 66(6):566-7. DOI: 10.1111/j.1399-0004.2004.00366.x. View

13.

Lynch P . The hMSH2 and hMLH1 genes in hereditary nonpolyposis colorectal cancer. Surg Oncol Clin N Am. 2009; 18(4):611-24. DOI: 10.1016/j.soc.2009.08.002. View

14.

Genuardi M, Anti M, Capozzi E, Leonardi F, Fornasarig M, Novella E . MLH1 and MSH2 constitutional mutations in colorectal cancer families not meeting the standard criteria for hereditary nonpolyposis colorectal cancer. Int J Cancer. 1998; 75(6):835-9. DOI: 10.1002/(sici)1097-0215(19980316)75:6<835::aid-ijc4>3.0.co;2-w. View

15.

Giraldez M, Balaguer F, Bujanda L, Cuatrecasas M, Munoz J, Alonso-Espinaco V . MSH6 and MUTYH deficiency is a frequent event in early-onset colorectal cancer. Clin Cancer Res. 2010; 16(22):5402-13. PMC: 3032288. DOI: 10.1158/1078-0432.CCR-10-1491. View

16.

Duraturo F, Liccardo R, Cavallo A, De Rosa M, Grosso M, Izzo P . Association of low-risk MSH3 and MSH2 variant alleles with Lynch syndrome: probability of synergistic effects. Int J Cancer. 2010; 129(7):1643-50. DOI: 10.1002/ijc.25824. View

17.

Nicolaides N, Papadopoulos N, Liu B, Wei Y, Carter K, Ruben S . Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature. 1994; 371(6492):75-80. DOI: 10.1038/371075a0. View

18.

Talseth-Palmer B, McPhillips M, Groombridge C, Spigelman A, Scott R . MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer. Hered Cancer Clin Pract. 2010; 8(1):5. PMC: 2890527. DOI: 10.1186/1897-4287-8-5. View

19.

Rumilla K, Schowalter K, Lindor N, Thomas B, Mensink K, Gallinger S . Frequency of deletions of EPCAM (TACSTD1) in MSH2-associated Lynch syndrome cases. J Mol Diagn. 2011; 13(1):93-9. PMC: 3069927. DOI: 10.1016/j.jmoldx.2010.11.011. View

20.

Morak M, Steinke-Lange V, Massdorf T, Benet-Pages A, Locher M, Laner A . Prevalence of CNV-neutral structural genomic rearrangements in MLH1, MSH2, and PMS2 not detectable in routine NGS diagnostics. Fam Cancer. 2020; 19(2):161-167. DOI: 10.1007/s10689-020-00159-4. View