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Lynch syndrome, MSH2 Sequencing and Deletion/Duplication (Including EPCAM)

Test code(s) 91471

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 detects single-nucleotide variants, deletions, and duplications in the MSH2 gene, which encodes the mismatch repair protein MSH2. It also analyzes 3’ deletions in the EPCAM gene, which are known to disrupt normal transcription of MSH2. Sample reports and information regarding the specific variants analyzed 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.

If immunohistochemical (IHC) analysis of mismatch repair proteins has been performed on certain tumor types, and loss of protein(s) is identified, germline testing of the corresponding gene(s) may be appropriate.

If Lynch syndrome is suspected but the familial mutation is not known and IHC analysis has not been performed, then testing for all Lynch genes with a multigene panel may be considered. Quest offers several multigene panels that include all Lynch genes: the Lynch Syndrome Panel [test code 91461], the Guideline-based Hereditary Cancer Panel [test code 38611], and the Comprehensive Hereditary Cancer Panel [test code 38600].

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).

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

Generally, this test may be indicated for individualswith a personal history a Lynch syndrome-related cancer when IHC analysis of mismatch repair proteins has been performed on the tumor and is suggestive of an inherited mutation in the MSH2 gene.1 Lynch syndrome-related cancers include colorectal, endometrial, gastric, ovarian, pancreas, ureter and renal pelvis, brain (usually glioblastoma), biliary tract, small intestinal cancers, in addition to sebaceous carcinomas and keratoacanthomas in Muir-Torre syndrome.

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–related 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, treatment or screening plan, personal experience with cancer, 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 detected in the MSH2 or EPCAM genes, and a diagnosis of Lynch syndrome. A positive result does not mean that an individual has a diagnosis of cancer. Pathogenic and likely pathogenic variants in MSH2 and EPCAM have an autosomal dominant pattern of inheritance, meaning that first-degree relatives have a 50% chance to have the same result. Rarely, if an individual inherits two different mutations (one from each parent) in MSH2 or EPCAM then they have a diagnosis of autosomal recessive constitutional mismatch repair deficiency (CMMRD).1 Specific risk information will be provided in the result report, and you can visit our website at www.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 the MSH2 or EPCAM genes. 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 tumors or cancer is based on their personal and family histories. Testing an affected family member may further inform this risk assessment. 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 this 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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