Test Catalog

Test Id : MLHPB

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MLH1 Hypermethylation Analysis, Blood

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Overview

Test Catalog

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

As an adjunct to positive hypermethylation in tumor to distinguish between somatic and germline hypermethylation

 

As an adjunct to negative MLH1 germline testing in cases where colon or endometrial tumor demonstrates microsatellite instability-H (MSI-H) and loss of MLH1 protein expression

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

For information see Lynch Syndrome Testing Algorithm.

Method Name
A short description of the method used to perform the test

Polymerase Chain Reaction (PCR)

NY State Available
Indicates the status of NY State approval and if the test is orderable for NY State clients.

Yes

Reporting Name
Lists a shorter or abbreviated version of the Published Name for a test

MLH1 Hypermethylation Analys, Blood

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

For information see Lynch Syndrome Testing Algorithm.

Specimen Type
Describes the specimen type validated for testing

Varies

Shipping Instructions

Specimen preferred to arrive within 96 hours of collection.

Specimen Required
Defines the optimal specimen required to perform the test and the preferred volume to complete testing

Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.

Container/Tube:

Preferred: Lavender top (EDTA) or yellow top (ACD)

Acceptable: Any anticoagulant

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send whole blood specimen in original tube. Do not aliquot.

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

Forms

1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file.

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

2. Molecular Genetics: Inherited Cancer Syndromes Patient Information (T519)

3. If not ordering electronically, complete, print, and send an Oncology Test Request (T729) with the specimen.

Specimen Minimum Volume
Defines the amount of sample necessary to provide a clinically relevant result as determined by the testing laboratory. The minimum volume is sufficient for one attempt at testing.

1 mL

Reject Due To
Identifies specimen types and conditions that may cause the specimen to be rejected

All specimens will be evaluated by Mayo Clinic Laboratories for test suitability.

Specimen Stability Information
Provides a description of the temperatures required to transport a specimen to the performing laboratory, alternate acceptable temperatures are also included

Specimen Type Temperature Time Special Container
Varies Ambient (preferred)
Refrigerated
Frozen

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

As an adjunct to positive hypermethylation in tumor to distinguish between somatic and germline hypermethylation

 

As an adjunct to negative MLH1 germline testing in cases where colon or endometrial tumor demonstrates microsatellite instability-H (MSI-H) and loss of MLH1 protein expression

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

For information see Lynch Syndrome Testing Algorithm.

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

Lynch syndrome/hereditary nonpolyposis colorectal cancer (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 EPCAM have also been associated with Lynch syndrome/HNPCC, as this leads to inactivation of the MSH2 promoter.

 

Lynch syndrome/HNPCC 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/HNPCC-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 PMS2 confer the lowest risk for any tumor within the Lynch syndrome/HNPCC spectrum.

 

Several clinical variants of Lynch syndrome/HNPCC 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 and central nervous system malignancies and sebaceous carcinomas, respectively. Homozygous mismatch repair mutations, characterized by the presence of biallelic 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 or family history of cancer is suggestive of Lynch syndrome/HNPCC. One such strategy involves testing the tumors from suspected individuals for microsatellite instability (MSI) and/or immunohistochemistry (IHC) for the presence or absence of defective DNA mismatch repair. However, it is important to note that the MSI-H tumor phenotype is not restricted to inherited cancer cases; approximately 20% of sporadic colon cancers are MSI-H. Thus, MSI-H does not distinguish between a somatic (sporadic) and a germline (inherited) mutation, nor does it identify which gene is involved. Although IHC analysis is helpful in identifying the responsible gene, it also does not distinguish between somatic and germline defects.

 

Defective mismatch repair in sporadic colon cancer is most often due to an abnormality in MLH1, and the most common cause of gene inactivation is promoter hypermethylation (epigenetic silencing). A specific mutation in BRAF (V600E) has been shown to be present in approximately 70% of tumors with hypermethylation of the MLH1 promoter. Importantly, the V600E mutation is rarely identified in cases with germline MLH1 mutations. Thus, direct assessment of MLH1 promoter methylation status and testing for the BRAF V600E mutation can be used to help distinguish between a germline mutation and epigenetic/somatic inactivation of MLH1. Tumors that have the BRAF V600E mutation and demonstrate MLH1 promoter hypermethylation are almost certainly sporadic, whereas tumors that show neither are most often caused by an inherited mutation.

 

However, individuals with tumor hypermethylation may additionally have MLH1 promoter hypermethylation consistent with germline inactivation. Individuals with germline inactivation of MLH1 by promoter hypermethylation are at an increased risk for Lynch syndrome/HNPCC-related tumors. In contrast to sequence mutations in MLH1, current evidence suggests that the risk of transmitting germline MLH1 promoter hypermethylation is <50%.

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.

Interpretive report will be provided.

Interpretation
Provides information to assist in interpretation of the test results

The report will include specimen information, assay information, and interpretation of test results.

 

Absence of hypermethylation is reported as not providing evidence for germline (constitutional) MLH1 promoter hypermethylation. Presence of hypermethylation is reported as consistent with germline (constitutional) inactivation of MLH1 by promoter hypermethylation.

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

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

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

1. Hitchins MP, Ward RL: Constitutional (germline) MLH1 epimutation as an aetiological mechanism for hereditary non-polyposis colorectal cancer. J Med Genet. 2009;46(12):793-802

2. Hitchins M, Williams R, Cheong K, et al: MLH1 germline epimutations as a factor in hereditary nonpolyposis colorectal cancer. Gastroenterology. 2005;129(5):1392-1399

3. Niessen RC, Hofstra RM, Westers H, et al: Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome. Genes Chromosomes Cancer. 2009;48(8):737-744

4. Valle L, Carbonell P, Fernandez V, et al: MLH1 germline epimutations in selected patients with early-onset non-polyposis colorectal cancer. Clin Genet. 2007;71(3):232-237

5. Idos G, Valle L: Lynch syndrome. In: Adam MP, Mirzaa GM, Pagon RA, et al, eds. GeneReviews (Internet). University of Washington, Seattle; 2004. Updated February 2, 2021. Accessed June 27, 2023. Available at www.ncbi.nlm.nih.gov/books/NBK1211/

Method Description
Describes how the test is performed and provides a method-specific reference

A polymerase chain reaction-based assay is used to test normal DNA for the presence of hypermethylation of the MLH1 promoter.(Grady WM, Rajput A, Lutterbaugh JD, Markowitz SD: Detection of aberrantly methylated hMLH1 promoter DNA in the serum of patients with microsatellite unstable colon cancer. Cancer Res. 2001 Feb;61(3):900-902)

PDF Report
Indicates whether the report includes an additional document with charts, images or other enriched information

No

Day(s) Performed
Outlines the days the test is performed. This field reflects the day that the sample must be in the testing laboratory to begin the testing process and includes any specimen preparation and processing time before the test is performed. Some tests are listed as continuously performed, which means that assays are performed multiple times during the day.

Varies

Report Available
The interval of time (receipt of sample at Mayo Clinic Laboratories to results available) taking into account standard setup days and weekends. The first day is the time that it typically takes for a result to be available. The last day is the time it might take, accounting for any necessary repeated testing.

8 to 12 days

Specimen Retention Time
Outlines the length of time after testing that a specimen is kept in the laboratory before it is discarded

Whole blood: 2 weeks (if available) Extracted DNA: 3 months

Performing Laboratory Location
Indicates the location of the laboratory that performs the test

Rochester

Fees :
Several factors determine the fee charged to perform a test. Contact your U.S. or International Regional Manager for information about establishing a fee schedule or to learn more about resources to optimize test selection.

  • Authorized users can sign in to Test Prices for detailed fee information.
  • Clients without access to Test Prices can contact Customer Service 24 hours a day, seven days a week.
  • Prospective clients should contact their account representative. For assistance, contact Customer Service.

Test Classification
Provides information regarding the medical device classification for laboratory test kits and reagents. Tests may be classified as cleared or approved by the US Food and Drug Administration (FDA) and used per manufacturer instructions, or as products that do not undergo full FDA review and approval, and are then labeled as an Analyte Specific Reagent (ASR) product.

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.

CPT Code Information
Provides guidance in determining the appropriate Current Procedural Terminology (CPT) code(s) information for each test or profile. The listed CPT codes reflect Mayo Clinic Laboratories interpretation of CPT coding requirements. It is the responsibility of each laboratory to determine correct CPT codes to use for billing.

CPT codes are provided by the performing laboratory.

81288

LOINC® Information
Provides guidance in determining the Logical Observation Identifiers Names and Codes (LOINC) values for the order and results codes of this test. LOINC values are provided by the performing laboratory.

Test Id Test Order Name Order LOINC Value
MLHPB MLH1 Hypermethylation Analys, Blood 97760-3
Result Id Test Result Name Result LOINC Value
Applies only to results expressed in units of measure originally reported by the performing laboratory. These values do not apply to results that are converted to other units of measure.
52906 Result Summary 50397-9
52907 Result 82939-0
52908 Interpretation 69047-9
52909 Reason for Referral 42349-1
52910 Specimen 31208-2
52911 Source 31208-2
52912 Released By 18771-6

Test Setup Resources

Setup Files
Test setup information contains test file definition details to support order and result interfacing between Mayo Clinic Laboratories and your Laboratory Information System.

Excel | Pdf

Sample Reports
Normal and Abnormal sample reports are provided as references for report appearance.

Normal Reports | Abnormal Reports

SI Sample Reports
International System (SI) of Unit reports are provided for a limited number of tests. These reports are intended for international account use and are only available through MayoLINK accounts that have been defined to receive them.

SI Normal Reports | SI Abnormal Reports

Test Update Resources

Change Type Effective Date
Test Changes - Specimen Information 2025-05-22