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Lynch Syndrome Panel

Test code(s) 91461

Question 1. What is the clinical application of this test?

This test is used to identify individuals with Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC) syndrome. It analyzes 5 genes: MLH1, MSH2, MSH6, PMS2, and EPCAM, which encode the mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2, respectively. 3’ deletions in EPCAM are known to disrupt transcription of MSH2. Sample reports and information regarding the specific variants analyzed for each gene are available on our website QuestHereditaryCancer.com.

Question 2. What other tests might be appropriate?

If a familial mutation has been detected by sequencing or deletion/duplication studies, the Hereditary Cancer Single Site(s) test [test code 93945] may be considered. Official test results of the family member must be available for laboratory review. For more information, please visit our website QuestHereditaryCancer.com. To discuss a family history with a Quest Diagnostics genetic counselor, please call Quest Genomics Client Services at 1.866.GENE.INFO (1.866.436.3463).

When immunohistochemical (IHC) analysis of the MMR proteins (MHL1, MSH2, MSH6, and PMS2) has been performed on certain tumor types, and loss of one or more of these proteins was identified, germline testing of only the corresponding gene(s) may be appropriate. The following single-gene tests are available: Lynch Syndrome, MLH1 Sequencing and Deletion/Duplication [test code 91460]; Lynch Syndrome, MSH2 Sequencing and Deletion/Duplication (Including EPCAM) [test code 91471]; Lynch Syndrome, MSH6 Sequencing and Deletion/Duplication [test code 91458]; and Lynch Syndrome, PMS2 Sequencing and Deletion/Duplication [test code 91457].

Question 3. What are the clinical indications for this testing?

Generally, this test may be indicated for individuals with any of the following1:

  • A personal or family history of colorectal, endometrial, ovarian, gastric, pancreatic, ureter and renal pelvis, brain (usually glioblastoma), biliary tract, and/or small intestinal cancers, sebaceous carcinomas, and keratoacanthomas
  • A personal history of colorectal or endometrial cancer with evidence of MMR deficiency, demonstrated either by microsatellite instability (MSI) or by loss of MMR protein expression via IHC analysis  
  • A personal history of colorectal tumor with MSI-high histology (ie, presence of tumor-infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet ring differentiation, or medullary growth pattern)
  • A ≥2.5% risk of having an MMR gene pathogenic variant based on predictive models (ie, PREMM5, MMRpro, MMRpredict)

Informed consent following genetic counseling is strongly recommended. Whenever possible, consider testing the person in the family with the youngest age at the time of diagnosis of a Lynch syndrome–associated cancer.

Question 4. Whom can I ask for help regarding a specific case?

For more information or to discuss a family history with a Quest genetic counselor, please call Quest Genomics Client Services at 1.866.GENE.INFO (1.866.436.3463).

Question 5. When is the right time to pursue this test?

The right time is different for every individual. An individual’s current medical status, personal experience with cancer, treatment or screening plan, and general readiness for genetic information all influence the decision to be tested. Having an open dialogue with individuals about these topics can assist with shared decision-making.

Question 6. How do I know if insurance will cover this testing?

Upon receipt of a fully completed order, our team will verify coverage with your patient’s healthcare insurance plan and estimate their likely out-of-pocket responsibility. If your patient’s estimated responsibility is over $100, we will notify you and/or your patient prior to test initiation to discuss options for continuation or cancellation of the test. Please note that orders lacking complete information will not be processed.

Question 7. How quickly can I expect results?

On average, results will be completed 14 to 21 days after receipt of the sample in the laboratory if the family history form and order are complete and the health plan does not require preauthorization. Turnaround time may vary based on delays caused by incomplete orders or insurance authorizations.

Question 8. What does a positive result mean?

Individuals with a positive result have a pathogenic or likely pathogenic variant(s) detected in the MLH1, MSH2, MSH6, PMS2, and/or EPCAM gene(s), and a diagnosis of Lynch syndrome.1 A positive result does not mean that an individual has a diagnosis of cancer. Pathogenic and likely pathogenic variants in these genes have an autosomal dominant pattern of inheritance, meaning that a first-degree relative has a 50% chance of having the same result. Rarely, if an individual inherits two different mutations (one from each parent) in the same gene they have a diagnosis of autosomal recessive constitutional MMR deficiency (CMMRD).1 Specific risk information will be provided in the result report, and you can visit our website at QuestHereditaryCancer.com for more information.

The National Comprehensive Cancer Network (NCCN®) provides up-to-date surveillance and management recommendations for individuals with a positive result.1

Question 9. What does a negative result mean?

A negative result means that a pathogenic or likely pathogenic variant was not detected in MLH1, MSH2, MSH6, PMS2, or deletions in 3’-EPCAM. For more information regarding specific genetic variants analyzed in this assay please refer to the methods and limitations section of the genetic testing report. Implications of this result depend on the situation:

Individual with previously diagnosed cancer: An individual’s risk of recurrence or a related new cancer is based on their personal and family histories of cancer. In some instances, it may be appropriate to test for other hereditary forms of cancer. Please call Quest Genomics Client Services at 1.866.GENE.INFO (1.866.436.3463)to discuss possible additional studies with a genetic counselor.

Individual without previously diagnosed cancer but with a family history of cancer: An individual’s risk of cancer is based on their personal and family histories of cancer. Testing an affected family member may further inform this risk assessment.1 In some instances, it may be appropriate to test for other hereditary forms of cancer. Please call Quest Genomics Client Services at 1.866.GENE.INFO (1.866.436.3463) to discuss possible additional studies with a genetic counselor.

Question 10. What does a variant of uncertain clinical significance (VUS) result mean?

A VUS result means that the variant has not been previously described in the literature or that the clinical significance is unclear based upon currently available evidence. Medical management decisions should be based on personal and family history. Family studies may help to learn more about the clinical significance of this variant. The classification and interpretation of the variant(s) identified reflect the current state of Quest’s understanding at the time of the report. Variant classification and interpretation are subject to professional judgment and may change for a variety of reasons including, but not limited to, updates in classification guidelines and availability of additional scientific and clinical information. It is important to check in with the laboratory annually for variant updates because new information regarding the variant and classification may become available over time. Please visit QuestDiagnostics.com/VariantIQ for information about variant classification. If you have questions, please call Quest Genomics Client Services at 1.866.GENE.INFO (1.866.436.3463)to speak with a genetic counselor.

Reference

  1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Genetic/familial high-risk assessment: colorectal. Version 3. 2019. Published December 19, 2019. https://www.nccn.org
This FAQ is provided for informational purposes only and is not intended as medical advice. A clinician’s test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.
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