Lynch Syndrome - Hereditary Nonpolyposis Colorectal Cancer (HNPCC)

Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), is an inherited cancer syndrome that predisposes an individual to colorectal, endometrial, gastric, ovarian, upper urinary tract, and other cancers. Patients with LS have a greater than 50% lifetime risk of developing colorectal cancer (CRC). LS results from pathogenic variants of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. In certain cases, a deletion of the EPCAM gene leads to MSH2 inactivation, and thus LS. Testing for LS includes screening for MMR deficiency in patients with CRC or endometrial tumors, as well as diagnostic germline genetic testing in patients with a personal and/or family history suggestive of LS.

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Clinical Overview

Quick Answers

What is the clinical presentation of Lynch syndrome?

Lynch syndrome (LS) often presents with early-onset colorectal cancer (CRC), in many cases before 50 years of age. Multiple tumors are common. Extracolonic tumors may also arise, depending on the specific causative pathogenic variant. Common extracolonic tumors include endometrial, prostate, ovarian, gastric, urinary tract, small bowel, hepatobiliary, brain/central nervous system, and pancreatic tumors, as well as sebaceous neoplasms.

Who should be tested for Lynch syndrome?

Several organizations recommend universal screening for Lynch syndrome (LS) in all patients with colorectal cancer (CRC)^, or endometrial cancer. Germline genetic testing is generally recommended for patients with an early cancer diagnosis, positive family history, and/or abnormal tumor testing results. The National Comprehensive Cancer Network (NCCN) has published specific criteria for Lynch syndrome screening (available at www.nccn.org).

When should molecular germline genetic testing for Lynch syndrome be performed?

In most situations, it is most cost-effective to first test for microsatellite instability (MSI) by polymerase chain reaction (PCR) and/or mismatch repair (MMR) protein deficiency by immunohistochemistry (IHC), as only 2-4% of colorectal cancer cases are Lynch syndrome (LS) associated. Both tests are sensitive and usually produce concordant results. If these tests reveal that a tumor has MSI or is MMR deficient, molecular germline genetic testing should be performed. However, if strong suspicion exists (eg, family history, cancer at a young age), it is reasonable to bypass MSI testing and proceed directly to molecular germline genetic testing.

Should BRAF testing be used for endometrial cancer specimens when screening for Lynch syndrome?

BRAF V600E testing is not appropriate for follow-up testing of endometrial cancer specimens with MLH1 loss by immunohistochemistry (IHC); only MLH1 promoter methylation testing should be performed. In colorectal cancer (CRC) specimens with MLH1 loss by IHC, BRAF V600E and MLH1 promoter methylation testing can be performed to determine the likelihood of Lynch syndrome (LS). See Screening of Cancer Specimens for more information, and the Lynch Syndrome (HNPCC) Testing Algorithm.

Lynch Syndrome (HNPCC) Testing Algorithm

Indications for Testing

Laboratory testing for LS is used to:

Screen for LS in all CRC specimens^,
Screen for LS in all endometrial tumors
Diagnose LS in patients with a suggestive personal or family history of tumors and/or cancer

Laboratory Testing

Screening of Cancer Specimens

In most situations, it is most effective to first perform somatic testing, ie, to evaluate specimens from patients with suspected LS with immunohistochemistry (IHC) or polymerase chain reaction (PCR) testing for MMR protein deficiency or microsatellite instability (MSI). This eliminates the expense of full gene sequencing for the majority of tumors that lack MMR deficiency, given that only 2-4% of CRCs are LS associated. Both IHC and PCR tests are sensitive and usually produce concordant results. However, if strong suspicion exists (eg, family history, cancer at a young age), it is reasonable to proceed with germline genetic testing.

Cancer Specimen (Somatic) Screening Tests for LS
Test	Characteristics	Test Interpretation
IHC	Involves staining of tumor tissue for protein expression of 4 MMR genes known to be mutated in LS (MLH1, MSH2, MSH6, and PMS2) Pattern of protein loss identified on IHC directs germline testing 5-10% false-negative rate NOTE: Loss of MLH1 may be due to acquired hypermethylation in sporadic tumors or a germline mutation in LS^a; see the Lynch Syndrome Testing (HNPCC) Algorithm for additional information	IHC Result	Likely Gene Mutation^a
		MLH1, PMS2 loss	MLH1 or, rarely, PMS2
		MSH2, MSH6 loss	MSH2 or, rarely, MSH6
		MSH6	MSH6 or MSH2
		PMS2	PMS2 or MLH1
MSI by PCR (panel of 5 or more mononucleotide microsatellites)	Detects expansion or contraction of microsatellite repeats in the tumor Does not detect which specific MMR protein is deficient Patient tumor tissue is compared with normal tissue Highest sensitivity achieved when PCR is combined with IHC Useful for MSI testing when IHC testing is negative despite high clinical suspicion of LS	Determination of MSI
		High (≥2 markers, or >30% of markers in an expanded panel, with instability): Consider germline testing IHC can be used to target specific LS gene for testing
		Low (1 marker, or <30% of markers in an expanded panel, with instability): IHC suggested Instability in even 1 mononucleotide repeat can be associated with LS
		Stable (no markers detected with instability): Very low risk of LS Add IHC and consider germline gene testing if high suspicion of LS exists
BRAF V600E or MLH1 promoter methylation	When MLH1 loss is identified using IHC, perform before LS mutation analysis Loss of MLH1 may be due to acquired hypermethylation in sporadic tumors or a germline mutation in LS NOTES: The BRAF V600E variant is uncommon in LS but common in sporadic CRC of the MSI pathway BRAF V600E testing is not appropriate for endometrial cancer; use only MLH1 promoter methylation testing Additional BRAF testing may be appropriate for sporadic CRC (see Colorectal Cancer topic)	If BRAF V600E or MLH1 hypermethylation is positive: LS unlikely; probably sporadic CRC Germline LS gene analysis not necessary unless high suspicion for LS still exists
^aRefer to Lynch Syndrome Testing (HNPCC) algorithm. NCCN, National Comprehensive Cancer Network Sources: Rubenstein, 2015; NCCN, 2019; Sepulveda, 2017; NCCN, 2019; Giardiello, 2014

Diagnosis

Molecular germline genetic testing is the gold standard for the diagnosis of LS. Genetic testing can be used in patients with suggestive screening results or if strong suspicion exists based on personal and/or family history. Germline gene analysis can take the form of single gene testing or a multigene panel. Consider single gene testing when IHC results indicate that a specific LS gene should be targeted. Consider a multigene panel if strong suspicion exists for LS or other hereditary cancer syndromes due to a suggestive personal and/or family history.

The diagnosis of LS is established by identification of a pathogenic variant in one of the MMR genes (MLH1, MSH2, MSH6, or PMS2) or an EPCAM deletion. Both sequencing and deletion/duplication analysis are necessary to identify all detectable pathogenic variants in MMR genes. If a pathogenic sequencing variant in an LS gene has already been identified in the family, targeted testing for the familial variant may be available (see ARUP test code 2001961).

Prognosis

Patients with MMR-deficient CRC have an improved prognosis compared with stage-matched patients without MMR deficiency.

ARUP Lab Tests

Preferred screening test for LS in individuals with CRC

Do not use in endometrial cancer

Mismatch Repair by Immunohistochemistry with Reflex to BRAF Codon 600 Mutation and MLH1 Promoter Methylation 2002327

Method: Qualitative Immunohistochemistry/Qualitative Real-time Polymerase Chain Reaction

First-line screening test for LS

Mismatch Repair by Immunohistochemistry 0049302

Method: Qualitative Immunohistochemistry

Screening test for LS

Microsatellite Instability (MSI), HNPCC/Lynch Syndrome, by PCR 0051740

Method: Polymerase Chain Reaction/Fragment Analysis

Recommended reflex test to differentiate between LS and sporadic CRC in tumors showing loss of MLH1

BRAF Codon 600 Mutation Detection with Reflex to MLH1 Promoter Methylation 0051750

Method: Polymerase Chain Reaction/ Pyrosequencing

Used within LS reflex testing pathway (for CRC specimens only)

BRAF Codon 600 Mutation Detection by Pyrosequencing 2002498

Method: Polymerase Chain Reaction/Pyrosequencing

Preferred reflex screening test for LS in non-CRC tumors (eg, endometrial carcinoma)

Mismatch Repair by Immunohistochemistry with Reflex to MLH1 Promoter Methylation 2005270

Method: Qualitative Immunohistochemistry/Qualitative Real-time Polymerase Chain Reaction

Recommended test to distinguish between LS and sporadic non-CRC tumors with loss of MLH1

MLH1 Promoter Methylation, Paraffin 2002499

Method: Real-Time Polymerase Chain Reaction/Fluorescence Resonance Energy Transfer

Recommended test to confirm a diagnosis of hereditary gastrointestinal (GI) cancer in individuals with a personal or family history of GI cancer and/or polyposis

Includes analysis of 5 LS genes (MLH1, MSH2, MSH6, PMS2, and EPCAM)

For additional test information, refer to the Hereditary Gastrointestinal Cancer Panel, Including Lynch Syndrome Test Fact Sheet

Hereditary Gastrointestinal Cancer Panel, Sequencing and Deletion/Duplication 2013449

Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray/Sequencing/Multiplex Ligation-dependent Probe Amplification

Useful when a pathogenic familial variant identifiable by sequencing is known

Familial Mutation, Targeted Sequencing 2001961

Method: Polymerase Chain Reaction/Sequencing

Detect germline MLH1 variants

HNPCC/Lynch Syndrome (MLH1) Sequencing and Deletion/Duplication 0051650

Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Detect germline MSH2 variants and EPCAM deletion

HNPCC/Lynch Syndrome (MSH2) Sequencing and Deletion/Duplication 0051654

Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Detect germline MSH6 variants

HNPCC/Lynch Syndrome (MSH6) Sequencing and Deletion/Duplication 0051656

Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Detect germline PMS2 variants

HNPCC/Lynch Syndrome (PMS2) Sequencing and Deletion/Duplication 0051737

Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Order if negative germline sequencing studies have been performed previously at another laboratory or if there is a known familial deletion or duplication

HNPCC/Lynch Syndrome Deletion/Duplication 2001728

Method: Polymerase Chain Reaction/Multiplex Ligation-dependent Probe Amplification

Test Fact Sheet(s)

Lynch Syndrome/Hereditary Nonpolyposis Colorectal Cancer

Hereditary Gastrointestinal Cancer Panel, Including Lynch Syndrome

Medical Experts

Bayrak-Toydemir, Pinar, MD, PhD, FACMG, Medical Director, Molecular Genetics and Genomics, at ARUP Laboratories; Professor of Clinical Pathology, University of Utah

Matynia, Anna P., MD, Medical Director, Solid Tumor Molecular Diagnostics, at ARUP Laboratories; Assistant Professor of Clinical Pathology, University of Utah

Wiley, Samantha, MS, LCGC, Genetic Counselor, Molecular Genetics, at ARUP Laboratories

References

Kohlmann W, Gruber S. Lynch Syndrome. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, editors. GeneReviews, University of Washington, 1993-2019. Seattle, WA [Last Revision: Apr 2018; Accessed: Dec 2019]
NCCN Clinical Practice Guidelines in Oncology, Genetic/Familial High-Risk Assessment: Colorectal. Version 2.2019. National Comprehensive Cancer Network. Fort Washington, PA [Updated: Aug 2019; Accessed: Dec 2019]
Rubenstein JH, Enns R, Heidelbaugh J, Barkun A, Clinical Guidelines Committee. American Gastroenterological Association Institute Guideline on the Diagnosis and Management of Lynch Syndrome. Gastroenterology. 2015; 149(3): 777-82; quiz e16-7. PubMed
Stoffel EM, Mangu PB, Gruber SB, Hamilton SR, Kalady MF, Lau MW, Lu KH, Roach N, Limburg PJ, American Society of Clinical Oncology, European Society of Clinical Oncology. Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines. J Clin Oncol. 2015; 33(2): 209-17. PubMed
Balmana J, Balaguer F, Cervantes A, Arnold D, ESMO Guidelines Working Group. Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines. Ann Oncol. 2013; 24 Suppl 6: vi73-80. PubMed
NCCN Clinical Practice Guidelines in Oncology, Colorectal Cancer Screening. Version 2.2019. National Comprehensive Cancer Network. Fort Washington, PA [Updated: Aug 2019; Accessed: Dec 2019]
Sepulveda AR, Hamilton SR, Allegra CJ, Grody W, Cushman-Vokoun AM, Funkhouser WK, Kopetz SE, Lieu C, Lindor NM, Minsky BD, Monzon FA, Sargent DJ, Singh VM, Willis J, Clark J, Colasacco C, Rumble B, Temple-Smolkin R, Ventura CB, Nowak JA. Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and the American Society of Clinical Oncology. J Clin Oncol. 2017; JCO2016719807. PubMed
NCCN Clinical Practice Guidelines in Oncology, Colon Cancer. Version 4.2019. National Comprehensive Cancer Network. Fort Washington, PA [Updated: Nov 2019; Accessed: Nov 2019]
Giardiello FM, Allen JI, Axilbund JE, Boland R, Burke CA, Burt RW, Church JM, Dominitz JA, Johnson DA, Kaltenbach T, Levin TR, Lieberman DA, Robertson DJ, Syngal S, Rex DK, US Multi-Society Task Force on Colorectal Cancer. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer. Gastroenterology. 2014; 147(2): 502-26. PubMed

Additional Resources

Bedeir A, Krasinskas AM. Molecular diagnostics of colorectal cancer. Arch Pathol Lab Med. 2011; 135(5): 578-87. PubMed

Boland R, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology. 2010; 138(6): 2073-2087.e3. PubMed

Djordjevic B, Broaddus RR. Role of the clinical pathology laboratory in the evaluation of endometrial carcinomas for Lynch syndrome. Semin Diagn Pathol. 2014; 31(3): 195-204. PubMed

Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med. 2009; 11(1): 35-41. PubMed

Geiersbach KB, Samowitz WS. Microsatellite instability and colorectal cancer. Arch Pathol Lab Med. 2011; 135(10): 1269-77. PubMed

Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL, Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Committee. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015; 17(1): 70-87. PubMed

Jasperson KW, Tuohy TM, Neklason DW, Burt RW. Hereditary and familial colon cancer. Gastroenterology. 2010; 138(6): 2044-58. PubMed

Legolvan MP, Taliano RJ, Resnick MB. Application of molecular techniques in the diagnosis, prognosis and management of patients with colorectal cancer: a practical approach. Hum Pathol. 2012; 43(8): 1157-68. PubMed

Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch JF, Boland CR. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet. 2009; 76(1): 1-18. PubMed

NCCN Clinical Practice Guidelines in Oncology, Uterine Neoplasms, Version 2.2019. National Comprehensive Cancer Network. Fort Washington, PA [Updated: Dec 2018; Accessed: Dec 2019]

Protocol for the Examination of Specimens from Patients with Primary Carcinoma of the Colon and Rectum. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: Oct 2013. College of American Pathologists (CAP). Northfield, IL [Revised: Jan 2016; Accessed: Dec 2019]

Rybak C, Hall MJ. Interpretation of genetic testing for lynch syndrome in patients with putative familial colorectal cancer. J Natl Compr Canc Netw. 2011; 9(11): 1311-20. PubMed

Senter L. Genetic testing by cancer site: colon (nonpolyposis syndromes). Cancer J. 2012; 18(4): 334-7. PubMed

Sharma SG, Gulley ML. BRAF mutation testing in colorectal cancer. Arch Pathol Lab Med. 2010; 134(8): 1225-8. PubMed

Vasen HF, Blanco I, Aktan-Collan K, Gopie JP, Alonso A, Aretz S, Bernstein I, Bertario L, Burn J, Capella G, Colas C, Engel C, Frayling IM, Genuardi M, Heinimann K, Hes FJ, Hodgson SV, Karagiannis JA, Lalloo F, Lindblom A, Mecklin J, Møller P, Myrhoj T, Nagengast FM, Parc Y, de Leon MP, Renkonen-Sinisalo L, Sampson JR, Stormorken A, Sijmons RH, Tejpar S, Thomas HJ, Rahner N, Wijnen JT, Järvinen HJ, Möslein G, Mallorca group. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut. 2013; 62(6): 812-23. PubMed

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Chadwick BE. Beyond cytomorphology: expanding the diagnostic potential for biliary cytology. Diagn Cytopathol. 2012; 40(6): 536-41. PubMed

Hegde M, Ferber M, Mao R, Samowitz W, Ganguly A, Working Group of the American College of Medical Genetics and Genomics (ACMG) Laboratory Quality Assurance Committee. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Genet Med. 2014; 16(1): 101-16. PubMed

Patil DT, Bronner MP, Portier BP, Fraser CR, Plesec TP, Liu X. A five-marker panel in a multiplex PCR accurately detects microsatellite instability-high colorectal tumors without control DNA. Diagn Mol Pathol. 2012; 21(3): 127-33. PubMed

Szankasi P, Reading S, Vaughn CP, Prchal JT, Bahler DW, Kelley TW. A quantitative allele-specific PCR test for the BRAF V600E mutation using a single heterozygous control plasmid for quantitation: a model for qPCR testing without standard curves. J Mol Diagn. 2013; 15(2): 248-54. PubMed

Tomsic J, Senter L, Liyanarachchi S, Clendenning M, Vaughn CP, Jenkins MA, Hopper JL, Young J, Samowitz W, de la Chapelle A. Recurrent and founder mutations in the PMS2 gene. Clin Genet. 2013; 83(3): 238-43. PubMed

Vaughn CP, Baker CL, Samowitz WS, Swensen JJ. The frequency of previously undetectable deletions involving 3' Exons of the PMS2 gene. Genes Chromosomes Cancer. 2013; 52(1): 107-12. PubMed

Walter AW, Ennis S, Best H, Vaughn CP, Swensen JJ, Openshaw A, Gripp KW. Constitutional mismatch repair deficiency presenting in childhood as three simultaneous malignancies. Pediatr Blood Cancer. 2013; 60(11): E135-6. PubMed

Testing Algorithms

Lynch Syndrome (HNPCC) Testing Algorithm

Read more about Lynch Syndrome (HNPCC) Testing Algorithm

Educational Videos

Content Review:

December 2019

Last Update: December 2019

Lynch Syndrome - Hereditary Nonpolyposis Colorectal Cancer (HNPCC)

Quick Answers

What is the clinical presentation of Lynch syndrome?

Who should be tested for Lynch syndrome?

When should molecular germline genetic testing for Lynch syndrome be performed?

Should BRAF testing be used for endometrial cancer specimens when screening for Lynch syndrome?

Lynch Syndrome (HNPCC) Testing Algorithm

Indications for Testing

Laboratory Testing

Screening of Cancer Specimens

Diagnosis

Prognosis

ARUP Lab Tests

Screening (Somatic)

Diagnosis (Germline)

Test Fact Sheet(s)

Medical Experts

References

Additional Resources

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Lynch Syndrome (HNPCC) Testing Algorithm

ARUP Laboratories

ARUP Websites

ARUP Consult


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Lynch Syndrome - Hereditary Nonpolyposis Colorectal Cancer (HNPCC)

Quick Answers

What is the clinical presentation of Lynch syndrome?

Who should be tested for Lynch syndrome?

When should molecular germline genetic testing for Lynch syndrome be performed?

Should BRAF testing be used for endometrial cancer specimens when screening for Lynch syndrome?

Lynch Syndrome (HNPCC) Testing Algorithm

Indications for Testing

Laboratory Testing

Screening of Cancer Specimens

Diagnosis

Prognosis

ARUP Lab Tests

Screening (Somatic)

Diagnosis (Germline)

Test Fact Sheet(s)

Medical Experts

References

Additional Resources

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Lynch Syndrome (HNPCC) Testing Algorithm

ARUP Laboratories

ARUP Websites

ARUP Consult