TEST CATALOG ORDERING & RESULTS SPECIMEN HANDLING CUSTOMER SERVICE EDUCATION & INSIGHTS
Test Catalog

Test ID: LYNCH    
Lynch Syndrome Panel, Varies

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

Establishing a diagnosis of Lynch syndrome

 

Identification of familial MLH1, MSH2, MSH6, PMS2, or EPCAM mutations to allow for predictive testing in family members

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

This test includes next-generation sequencing, Sanger sequencing, array comparative genomic hybridization, and multiplex ligation-dependent probe amplification to evaluate for mutations and large deletions/duplications in the MLH1, MSH2, MSH6, PMS2, and EPCAM genes. Sanger sequencing may also be performed to confirm detected variants.

 

Prior Authorization is available for this assay; see Special Instructions.

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

See Lynch Syndrome Testing Algorithm in Special Instructions.

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

While the risk for colorectal cancer in the general population is 6%, rarely colon cancer is attributable to hereditary factors associated with a single abnormal gene that predisposes individuals to increased risks for cancer in a family.

 

Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer or HNPCC) 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' end of the EPCAM gene, which lead to inactivation of the MSH2 promotor, have also been associated with Lynch syndrome.

 

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. 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 less than 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.

 

The National Comprehensive Cancer Network and the American Cancer Society provide recommendations regarding the medical management of individuals with Lynch syndrome.

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

All detected alterations are evaluated according to American College of Medical Genetics and Genomics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

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

Clinical Correlations:

Some individuals who have a hereditary susceptibility to breast cancer may have a mutation that is not identified by this method (eg, promoter mutations, deep intronic mutations). The absence of a mutation, therefore, does not eliminate the possibility of a hereditary susceptibility to breast cancer in the individual or family. For predictive testing, it is important to first document the presence of a gene mutation in an affected family member.

 

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 is inaccurate or incomplete. We strongly recommend that patients undergoing predictive testing receive genetic counseling both prior to testing and after results are available.

 

Technical Limitations:

In some cases, DNA variants of undetermined significance may be identified. Due to the limitations of next-generation sequencing, we can detect greater than 93% of insertions and deletions up to 20 bases and 43 bases, respectively. If a diagnosis is still suspected, consider full gene sequencing using traditional Sanger methods. Single or multiexon deletions as well as whole gene deletions will be detected by array comparative genomic hybridization (aCGH) or multiplex ligation-dependent probe amplification (MLPA). Rare polymorphisms exist that could lead to false-negative or false-positive results.

 

If results obtained do not match the clinical findings, additional testing should be considered.

  

Evaluation Tools:

Multiple in-silico evaluation tools were used to assist in the interpretation of these results. These tools are updated regularly; therefore, changes to these algorithms may result in different predictions for a given alteration. Additionally, the predictability of these tools for the determination of pathogenicity is currently not validated.

 

Unless reported or predicted to cause disease, alterations found deep in the intron or alterations that do not result in an amino acid substitution are not reported. These and common polymorphisms identified for this patient are available upon request.

 

Reclassification of Variants-Policy:

All detected alterations are evaluated according to American College of Medical Genetics and Genomics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. At this time, it is not standard practice for the laboratory to systematically re-review likely deleterious alterations or variants of uncertain significance that are detected and reported. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time.

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

1. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015 May;17(5):405-424

2. Lindor NM, McMaster ML, Lindor CJ, et al: Concise Handbook of Familial Cancer Susceptibility Syndromes. Second edition. J Natl Cancer Inst Monogr 2008;(38):1-93

3. Lynch Syndrome-GeneReviews-NCBI Bookshelf. Accessed 6/1/2015. Available at www.ncbi.nlm.nih.gov/books/NBK1211/

4. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Genetic/Familial High-Risk Assessment: Colorectal Version 2.2014. Accessed 6/1/2015. Available at www.nccn.org

5. Vasen HFA, 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

6. Baglietto L, Lindor NM, Dowty JG, et al: Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst 2010 Feb3;102(3):193-201

7. Senter L, Clendenning M, Sotamaa K, et al: The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology 2008;135:419-428

8. Vaughn CP, Hart J, Samowitz WS, Swensen JJ: Avoidance of pseudogene interference in the detection of 3' deletions in PMS2. Hum Mutat 2011;32:1063-1071

9. Clendenning M, Hampel H, LaJeunesse J, et al: Long-range PCR facilitates the identification of PMS2-specific mutations. Hum Mutat 2006;27(5):490-495

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