Test Catalog

Test ID: IHC    
Mismatch Repair (MMR) Protein Immunohistochemistry Only, Tumor

Useful For Suggests clinical disorders or settings where the test may be helpful

Evaluation of tumor tissue to identify patients at risk for having hereditary nonpolyposis colon cancer/Lynch syndrome

Testing Algorithm Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

When this test is ordered, MLH1, MSH2, MSH6, and PMS2 stains will always be performed at an additional charge.


See Lynch Syndrome Testing Algorithm in Special Instructions.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Hereditary nonpolyposis colon cancer (HNPCC), also known as Lynch syndrome, is an autosomal dominant inherited cancer syndrome that predisposes individuals to the development of colorectal, endometrial, gastric, upper urinary tract, and other cancers. Individuals with HNPCC/Lynch syndrome have a germline mutation in 1 of several genes involved in DNA mismatch repair. The majority of mutations associated with HNPCC/Lynch syndrome occur in MSH2 and MLH1; however, mutations in MSH6 and PMS2 have also been identified.


There are several strategies for evaluating individuals whose personal or family history of cancer is suggestive of HNPCC/Lynch syndrome. Typically, the first step is to evaluate tumors for the characteristics common to individuals with HNPCC/Lynch syndrome, which include microsatellite instability (presence of numerous alterations in a type of repetitive DNA called microsatellites) and loss of protein expression of 1 or more of the genes associated with HNPCC/Lynch syndrome.


Microsatellite instability (MSI) and immunohistochemistry (IHC) are commonly interpreted together to evaluate risk for HNPCC/Lynch syndrome. High levels of MSI within a tumor are suggestive of defective DNA mismatch repair,

however, this finding does not provide information about which gene is involved. IHC is a complementary testing strategy used to evaluate the expression of the MLH1, MSH2, MSH6, and PMS2 proteins in HNPCC/Lynch syndrome-related cancers. Loss of expression of 1 or more of these proteins within the tumor is helpful in identifying which corresponding genes to target for mutation analysis. Although MSI and IHC are best interpreted together, they are also available separately to accommodate clinical situations in which there are barriers to performing these tests concurrently (eg, financial concerns, specimen requirements).


IHC alone can determine retention or loss of MLH1, MSH2, MSH6, and PMS2 protein expression. If all 4 proteins are present, the likelihood of HNPCC/Lynch syndrome is reduced, but not eliminated, because approximately 5% of tumors that display MSI also have normal protein expression for these 4 genes. Loss of 1 or more proteins by IHC is suggestive of defective DNA mismatch repair within the tumor and the likelihood of HNPCC/Lynch syndrome is increased. Germline testing (ie, mutation analysis) for the corresponding genes can then be performed to identify the causative germline mutation and allow for predictive testing of at risk individuals.


Of note, loss of protein expression by IHC has also been demonstrated in various sporadic cancers, including those of the colon and endometrium. Absence of MLH1 and PMS2 protein expression within a tumor, for instance, is most often associated with a somatic alteration in individuals with an older age of onset of cancer than typical HNPCC/Lynch syndrome families. Therefore, an MSI-H phenotype or loss of protein expression by IHC within a tumor does not distinguish between somatic and germline mutations. Genetic testing of the gene indicated by IHC analysis can help to distinguish between these 2 possibilities. In addition, when absence of MLH1 and PMS2 are observed, the BRMLH / MLH1 Hypermethylation and BRAF Mutation Analysis, Tumor or ML1HM / MLH1 Hypermethylation Analysis, Tumor test may also help to distinguish between a sporadic and germline etiology.


It should be noted that this is not a genetic test, but rather stratifies the risk of having an inherited cancer predisposition syndrome, and identifies patients who might benefit from subsequent genetic testing.


See Lynch Syndrome Testing Algorithm in Special Instructions for additional information.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

An interpretive report will be provided.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

The finding of absent protein expression for 1 or more of the MMR genes tested does not distinguish between somatic and germline mutations.


Because immunohistochemistry (IHC) results may indicate likelihood of a germline alteration, it is recommended that genetic counseling be provided prior to IHC testing.


Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors may occur in our interpretation of results if information given to us is inaccurate or incomplete.

Supportive Data

Over 1,000 patients who have colorectal cancer have been evaluated for these genetic alterations by our laboratory staff (1/2006).

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Baudhuin LM, Burgart LJ, Lentovich O, Thibodeau SN: Use of microsatellite instability and immunohistochemistry testing for the identification of individuals at risk for Lynch Syndrome. Fam Cancer 2005;4(3):255-265

2. Shia J, Klimstra DS, Nafa K, et al: Value of immunohistochemical detection of DNA mismatch repair proteins in predicting germline mutation in hereditary colorectal neoplasms. Am J Surg Pathol 2005;29:96-104

Special Instructions Library of PDFs including pertinent information and forms related to the test