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Lynch Syndrome - Hereditary Nonpolyposis Colorectal Cancer (HNPCC) . ARUP Consult®. Retrieved October 05, 2025, https://arupconsult.com/content/lynch-syndrome

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Lynch Syndrome - Hereditary Nonpolyposis Colorectal Cancer (HNPCC)

Last Literature Review: April 2025 Last Update:

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Matynia

Anna P. Matynia, MD
Anna P. Matynia, MD
Associate Professor of Pathology (Clinical), University of Utah
Section Chief, Solid Tumor Molecular Oncology, ARUP Laboratories

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. The risk of developing one of these cancers and the age of onset vary, depending on the associated gene.  LS results from pathogenic variants in the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. In certain cases, a deletion of the promoter region 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

Which patients with cancer should be tested for Lynch syndrome?

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. 

When should germline genetic testing for Lynch syndrome be performed?

In most situations, it is cost-effective to perform somatic testing for mismatch repair (MMR) protein deficiency by immunohistochemistry (IHC) and/or microsatellite instability (MSI) by polymerase chain reaction (PCR) before germline testing, given that only a small percentage of colorectal and endometrial cancer cases are Lynch syndrome (LS) associated. ,  Both tests are sensitive and usually produce concordant results. If these tests reveal that a tumor is MMR deficient or has MSI, follow-up somatic molecular testing and/or germline genetic testing should be performed. However, if strong suspicion for LS exists (e.g., due to family history or cancer at a young age) or tissue availability is limited, it is reasonable to bypass MSI testing and proceed directly to molecular germline genetic testing. , 

When should genetic testing be considered in family members of individuals diagnosed with Lynch syndrome?

Patients should be advised to communicate with family members about the possibility of inherited cancer susceptibility, as well as options for testing and management. Genetic counseling and consideration of appropriate cascade genetic testing should be recommended for relatives at risk. 

Indications for Testing

Testing for LS is indicated in individuals with:

  • Colon or endometrial cancer - 
  • A personal or family history suggestive of LS 
  • A relative with a known LS-associated pathogenic gene variant 
  • An identified pathogenic/likely pathogenic (P/LP) variant in tumor tissue that has clinical implications if also detected in the germline 

Laboratory Testing

Screening of Cancer Specimens

In most situations, it is most effective to first perform somatic testing, i.e., to evaluate specimens with immunohistochemistry (IHC) or polymerase chain reaction (PCR) testing for MMR protein deficiency/microsatellite instability (MSI). However, if strong suspicion exists (e.g., due to family history or 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, refer to the Lynch Syndrome (HNPCC) Testing algorithm.

Cancer Specimen (Somatic) Screening Tests for LS
TestUse and Characteristics 
MMR by IHC

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

The pattern of protein loss directs germline testing (refer to the Diagnosis section)

 
MSI by PCR

Useful when IHC testing is negative despite high clinical suspicion

Does not detect which MMR protein is deficient

 
BRAF V600E by PCR (in cases of CRC; not applicable for endometrial cancer)

Use when the absence of MLH1 expression is identified by IHC; perform before germline testinga (refer to the Diagnosis section)

If either BRAF V600E variant or MLH1 promoter methylation is positive, cancer is likely sporadic CRC

 
MLH1 promoter methylation by real-time PCR/fluorescence resonance energy transfer

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

 

aIf loss of MLH1 expression is concurrent with loss of MSH2 or MSH6 expression, germline genetic analysis is appropriate. 

Sources: NCCN, 2025 ; Rubenstein, 2015 ; ESMO, 2019 ; NCCN, 2024 ; Sepulveda, 2017 ; NCCN, 2025 ; Giardiello, 2014 

 

Diagnosis

Molecular germline genetic testing can be used for definitive 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 germline multigene panel if strong suspicion exists for LS or other hereditary cancer syndromes due to a suggestive personal and/or family history. Ideally, germline genetic testing should be performed in the context of formalized genetic counseling, with an affected family member tested first. This enables targeted genetic testing for any causative variant(s) identified in affected family members. Panel testing may be important to consider in patients who were tested previously using only single gene analysis (e.g., MLH1 or MSH2 only). , 

The diagnosis of LS is established by the 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. Ruling out a germline variant in patients with MMR deficiency or MSI (excluding MLH1 hypermethylation) is important, as it prevents intensive surveillance of Lynch-associated tumors in relatives otherwise identified as potentially at risk. 

It is important to note that sequencing performed on somatic tumor tissue will not detect some variants (e.g., deletions/duplications, splicing variants) that are clinically actionable. 

ARUP Laboratory Tests

Screening (Somatic)

Diagnosis (Germline)

For additional test information, refer to the Lynch Syndrome Panel, Sequencing and Deletion/Duplication Test Fact Sheet

For additional test information, refer to the Hereditary Gastric Cancer Panel, Sequencing and Deletion/Duplication Test Fact Sheet

References