Interpretive Handbook

Test 17073 :
Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Screen

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

Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is an autosomal dominant hereditary cancer syndrome associated with germline mutations in the mismatch repair genes, MLH1, MSH2, MSH6, and PMS2. Deletions within the 3-prime end of the EPCAM gene have also been associated with HNPCC/Lynch syndrome, as this leads to inactivation of the MSH2 promoter.


Lynch syndrome is predominantly characterized by significantly increased risks for colorectal and endometrial cancer. The lifetime risk for colorectal cancer is highly variable and dependent on the gene involved. The risk for colorectal cancer associated MLH1 and MSH2 mutations (approximately 50%-80%) is generally higher than the risks associated with mutations in the other Lynch syndrome related genes and the lifetime risk for endometrial cancer (approximately 25%-60%) is also highly variable. Other malignancies within the tumor spectrum include gastric cancer, ovarian cancer, hepatobiliary and urinary tract carcinomas, and small bowel cancer. The lifetime risks for these cancers are <15%. Of the 4 mismatch repair genes, mutations within the PMS2 gene confer the lowest risk for any of the tumors within the Lynch syndrome spectrum.


Several clinical variants of Lynch syndrome have been defined. These include Turcot syndrome, Muir-Torre syndrome, and homozygous mismatch repair mutations (also called constitutional mismatch repair deficiency syndrome). Turcot syndrome and Muir-Torre syndrome are associated with increased risks for cancers within the tumor spectrum described but also include brain/central nervous system malignancies and sebaceous carcinomas, respectively. Homozygous mismatch repair mutations, characterized by the presence of bi-allelic deleterious mutations within a mismatch repair gene, are associated with a different clinical phenotype defined by hematologic and brain cancers, cafe au lait macules, and childhood colon or small bowel cancer.


There are several strategies for evaluating individuals whose personal and/or family history of cancer is suggestive of HNPCC/Lynch syndrome. Testing tumors from individuals at risk for HNPCC/Lynch syndrome for microsatellite instability (MSI) indicates the presence or absence of defective DNA mismatch repair within the tumor. Individuals whose tumors demonstrate the presence of defective DNA mismatch repair in the form of microsatellite instability are more likely to have a germline mutation in 1 of the mismatch repair genes, MLH1, MSH2, MSH6, and PMS2. Tumors from affected individuals usually demonstrate an MSI-H phenotype (MSI >30% of microsatellites examined), whereas tumors from individuals who do not have HNPCC/Lynch syndrome usually have an MSS/MSI-L phenotype (MSI at <30% of microsatellites examined). Immunohistochemistry (IHC) is a complementary testing strategy to MSI testing. In addition to identifying tumors with defective DNA mismatch repair, IHC analysis is helpful for identifying the gene responsible for the defective DNA mismatch repair within the tumor, because the majority of MSI-H tumors show a loss of expression of at least 1 of the 4 mismatch repair genes described above.


Testing is typically first performed on the tumor of an affected individual and in the context of other risk factors, such as young age at diagnosis or a strong family history of HNPCC/Lynch syndrome-related cancers. If defective DNA mismatch repair is identified within the tumor, mutation analysis of the associated gene can be performed to identify the causative germline mutation and allow for predictive testing of at risk individuals.


Of note, MSI-H phenotypes and loss of protein expression by IHC have 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 two possibilities. In addition, when absence of MLH1/PMS2 is observed, MLBRF / MLH1 Hypermethylation and BRAF Mutation Analyses, Tumor or MLH1H / MLH1 Hypermethylation Analysis, Tumor may also help to distinguish between a sporadic and germline etiology.


It should be noted that this HNPCC screen 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 Hereditary Nonpolyposis Colorectal Cancer Testing Algorithm in Special Instructions for additional information.

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

Identification of individuals at high risk for having hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome

Interpretation Provides information to assist in interpretation of the test results

The report will include specimen information, assay information, and interpretation of test results. Microsatellite stable (MSS) is reported as MSS/MSI-L (0 or 1 of 5 markers demonstrating instability) or MSI-H (2 or more of 5 markers demonstrating instability).

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

Owing to the sensitive and complicated nature of cancer risk stratification testing, it is strongly recommended that testing be performed in conjunction with appropriate pre- and post-test counseling.


The finding of tumor microsatellite instability or the absence of protein expression for MSH2, MSH6, MLH1, or PMS2 does not distinguish between somatic and germline mutations.


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

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.

Clinical References Provides recommendations for further in-depth reading of a clinical nature

1. Baudhuin LM, Burgart LJ, Leontovich 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. Terdiman JP, Gum JR Jr, Conrad PG, et al: Efficient detection of hereditary nonpolyposis colorectal cancer gene carriers by screening for tumor microsatellite instability before germline genetic testing. Gastroenterology 2001 January;120(1):21-30

3. Vasen HF, Moslein G, Alonso A, et al: Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet 2007;44:353-362

4. Lynch Syndrome–GeneReviews–NCBI Bookshelf. Available from URL: