Associated disorders

The MLH3 gene has preliminary evidence supporting a correlation with autosomal dominant Lynch syndrome.

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MLH1 is a member of a group of DNA mismatch repair (MMR) genes, which encode proteins that detect and repair DNA mismatches that can occur during cell replication. This complex coordinates the activities of other proteins that repair mistakes made during DNA replication.

MLH3 heterozygote
OMIM: 604395

Clinical condition
The MLH3 gene currently has no well-established disease association; however, there is preliminary evidence supporting a correlation with autosomal dominant Lynch syndrome (PMID: 11586295, 12702580). These data, however, are currently insufficient to make a clear determination regarding this association. Therefore, MLH3 is considered a “preliminary-evidence” gene and is available on Invitae’s Colorectal Cancer Panel. Preliminary-evidence genes are selected from an extensive review of the literature and expert recommendations, but the association between the gene and the specific condition has not been completely established. This uncertainty may be resolved as new information becomes available, and therefore clinicians may continue to order these preliminary-evidence genes.

Gene information
MLH3 is one of several DNA mismatch repair (MMR) genes. These genes encode proteins that detect and repair DNA mismatches that can occur during cell replication. The protein encoded by MLH3 functions as a heterodimer with MSH2. Somatic mutations in this gene frequently occur in tumors exhibiting microsatellite instability, and germline mutations have been linked to Lynch syndrome (NCBI. Gene. Gene ID: 27030. Accessed March 2016).

Variants in MLH3 have autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing that variant on to their offspring.

Because the evidence regarding MLH3 and Lynch syndrome is limited and preliminary, there are no guidelines or recommendations to suggest alteration to medical management based solely on the presence of a MLH3 variant. However, an individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors including personal medical history, family history, and any available genetic information that may result in a personalized plan for cancer prevention and surveillance.

Even though data regarding MLH3 are limited, knowing if a pathogenic variant is present is advantageous. At-risk relatives can be identified, allowing pursuit of a diagnostic evaluation. In addition, the available information regarding hereditary cancer susceptibility genes is constantly evolving and clinically relevant MLH3 data is likely to become available in the near future. Awareness of this variant encourages patients and their providers to inform at-risk family members, to consider implementing established screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.

Review date: March 2016

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
MLH3 NM_001040108.1