Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), is an inherited cancer syndrome that predisposes an individual to early-onset colorectal cancer, endometrial, gastric, ovarian, upper urinary tract, and other cancers. The risk of developing one of these cancers varies, depending on the associated gene. 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 colorectal cancer (CRC) or endometrial tumors, as well as diagnostic germline genetic testing in patients with a personal and/or family history suggestive of LS.
Quick Answers for Clinicians
Several organizations recommend universal screening for Lynch syndrome (LS) in all patients with endometrial cancer or colorectal cancer (CRC). - 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 LS screening (available at www.nccn.org).
In most situations, it is cost-effective to perform somatic testing for microsatellite instability (MSI) by polymerase chain reaction (PCR) and/or mismatch repair (MMR) protein deficiency by immunohistochemistry (IHC) before germline testing, given that 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 for LS exists (eg, family history, cancer at a young age), it is reasonable to bypass MSI testing and proceed directly to molecular germline genetic testing.
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
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). However, if strong suspicion exists (eg, family history, cancer at a young age), it is reasonable to proceed directly to germline genetic testing.
For more detailed interpretive information about the screening tests for LS, see the Lynch Syndrome (HNPCC) Testing algorithm.
|Test||Use and Characteristics|
Mismatch repair by immunohistochemistry
Use as initial test when screening cancer specimen for Lynch syndrome
Stains for protein expression of 4 MMR genes (MLH1, MSH2, MSH6, and PMS2)
Eliminates the expense of full gene sequencing for the majority of tumors that lack MMR deficiency
Pattern of protein loss directs germline testing (see Diagnosis)
Microsatellite instability by PCR
Useful when IHC testing is negative despite high clinical suspicion
Does not detect which MMR protein is deficient
BRAF V600E by PCR/pyrosequencing
Use when MLH1 loss is identified by IHC; perform before germline testing (see Diagnosis)
If either BRAF V600E variant or MLH1 promoter methylation is positive, cancer is likely sporadic CRC
BRAF V600E and MLH1 promoter methylation testing may be ordered together as a reflex test
BRAF V600E testing is not appropriate for endometrial cancer; use only MLH1 promoter methylation testing
MLH1 promoter methylation by real-time PCR/fluorescence resonance energy transfer
Sources: NCCN, 2021 ; Rubenstein, 2015 ; NCCN, 2022 ; Sepulveda, 2017 ; NCCN, 2022 ; Giardiello, 2014
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. Single gene testing can be considered 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.
ARUP Laboratory Tests
Polymerase Chain Reaction/Pyrosequencing
Real-Time Polymerase Chain Reaction/Fluorescence Resonance Energy Transfer
Massively Parallel Sequencing/Sequencing/Multiplex Ligation-Dependent Probe Amplification (MLPA)
Massively Parallel Sequencing/Sequencing/Multiplex Ligation-dependent Probe Amplification
For additional test information, refer to the Hereditary Gastric Cancer Panel, Sequencing and Deletion/Duplication Test Fact Sheet
Multiplex Ligation-dependent Probe Amplification
GeneReviews - Lynch Syndrome
Idos G, Valle L. Lynch syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews, University of Washington; 1993-2021. [Last revision: Feb 2021; Accessed: Nov 2021]
NCCN - genetic/familial high-risk: colorectal v2.2021
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: genetic/familial high-risk assessment—colorectal. Version 2.2021. [Updated: Apr 2022; Accessed: Oct 2022]
Rubenstein JH, Enns R, Heidelbaugh J, et al. American Gastroenterological Association Institute guideline on the diagnosis and management of Lynch syndrome. Gastroenterology. 2015;149(3):777-782; quiz e16-17.
Stoffel EM, Mangu PB, Gruber SB, et al. 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):209-217.
Balmana J, Balaguer F, Cervantes A, et al. Familial risk-colorectal cancer: ESMO clinical practice guidelines. Ann Oncol. 2013;24 Suppl 6: vi73-vi80.
NCCN - Colorectal cancer screening v1.2022
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Colorectal cancer screening. Version 1.2022. [Updated: Mar 2022; Accessed: Oct 2022]
Sepulveda AR, Hamilton SR, Allegra CJ, et al. 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;35(13):1453-1486.
NCCN - Colon cancer v1.2022
National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: colon cancer. Version 1.2022. [Updated: Feb 2022; Accessed: Oct 2022]
Giardiello FM, Allen JI, Axilbund JE, et al. 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):502-526.
NCCN - Uterine Neoplasms - Lynch Syndrome
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Uterine neoplasms. Version 1.2021. [Updated: Oct 2020; Accessed: Feb 2021]
CAP - Primary Carcinoma of the Colon and Rectum
College of American Pathologists (CAP). Protocol for the examination of specimens from patients with primary carcinoma of the colon and rectum. [Posted: Feb 2020; Accessed: Mar 2021]
For additional test information, refer to the Lynch Syndrome Panel, Sequencing and Deletion/Duplication Test Fact Sheet