Interpretive Handbook

Test 61472 :
MLH3 Gene, Full Gene Analysis

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, resulting in microsatellite instability (MSI), 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.

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

Testing for mutations in all 12 exons of the MLH3 gene

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

A percentage of individuals may have a mutation that is not identified by this method (eg, promoter mutations, deep intronic alterations). The absence of a mutation, therefore, does not eliminate the possibility of an increased risk for colorectal cancer.


In some cases, DNA alterations of undetermined significance may be identified.


We strongly recommend that asymptomatic 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.


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.


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.


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.


In addition to disease-related probes, the array comparative genomic hybridization (aCGH) technique utilizes probes localized to other chromosomal regions as internal controls. In certain circumstances, these control probes may detect other diseases or conditions for which this test was not specifically intended. Results of the control probes are not normally reported. However, in cases where clinically relevant information is identified, the ordering physician will be informed of the result and provided with recommendations for any appropriate follow-up testing.

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