Interpretive Handbook

Test 61473 :
MLH3 Gene, Known Mutation

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

MLH3 is a gene that has been investigated in regards to its role in hereditary colorectal cancer. Current literature suggests that alterations in the MLH3 gene are found more often in the disease population than in healthy controls. Therefore, individuals with a mutation in MLH3 may be at an increased risk for colorectal cancer. However, mutations in MLH3 have been seen in both family members with disease and healthy relatives, indicating reduced penetrance. Also, it has been suggested that MLH3 is a low-risk gene for colorectal cancer. When mutations in MLH3 are seen with mutations in other genes associated with colorectal cancer, the genes may work in an additive manner further elevating risk.


In addition to patients with colorectal cancer, MLH3 alterations have been reported in individuals with endometrial and esophageal cancers. Current literature suggests that in some families MLH3 may act as a low-risk gene for esophageal cancer. Additionally, MLH3 may play a role in endometrial tumorigenesis, with involvement in initiation and/or progression of endometrial cancers.  


There is conflicting evidence in the literature regarding the ability of mutations in MLH3 to alter mismatch repair (MMR). Some studies suggest that MLH3 mutations can affect DNA mismatch repair, while others say mutations in MLH3 alone do not interfere with MMR. Alterations have been reported in both microsatellite stable (MSS)/MSI-low tumors and MSI-high tumors. However, some of these MSI-H tumors also had loss reported with immunohistochemistry. Additional research is needed to fully understand the relationship between MLH3 mutations and MSI status.


Note: This test is appropriate for predictive testing in families in which a point mutation or small insertion/deletion/duplication has been identified. SDEL / Single-Gene Large Deletion and Duplication Analysis is appropriate for predictive testing in families in which a large deletion or duplication (whole exon or multiexon) has been identified. If a familial mutation has not been previously identified, full analysis of the MLH3 gene is more appropriate (see MLH3S / MLH3 Gene, Full Gene Analysis).

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

Testing for MLH3 when a point mutation or small insertion/deletion/duplication has been identified previously in an affected family member

Interpretation Provides information to assist in interpretation of the test results

All detected alterations are evaluated according to American College of Medical Genetics (ACMG) 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

The identification of a disease-causing mutation in an affected family member is necessary before predictive testing for other family members can be offered. If a familial mutation has not been previously identified, order MLH3S / MLH3 Gene, Full Gene Analysis.


Analysis is performed for the familial mutation provided only. This assay does not rule out the presence of other mutations within this gene or within other genes that may be associated with hereditary colorectal cancer.


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


Predictive testing of an asymptomatic child is not recommended.


Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Any error in the diagnosis or in the pedigree provided to us, including false-paternity, could lead to erroneous interpretation of results.


A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.


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.

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. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008;10(4):294-300

2. Liu HX, Zhou XL, Liu T, et al: The role of hMLH3 in familial colorectal cancer. Cancer Res 2003;63(8):1894-1899

3. Liu HX, Li Y, Jiang XD, et al: Mutation screening of mismatch repair gene Mlh3 in familial esophageal cancer. World J Gastroenterol 2006;2(33):5281-5286

4. Taylor NP, Powell MA, Gibb RK, et al: MLH3 mutation in endometrial cancer. Cancer Res 2006;66(15):7502-7508