COCA2; FCC2; HNPCC; HNPCC2; hMLH1
The MLH1 gene is associated with autosomal dominant Lynch syndrome (also called hereditary nonpolyposis colorectal cancer syndrome, or HNPCC) (MedGen UID: 232603) and autosomal recessive constitutional mismatch repair deficiency syndrome (CMMR-D) (MedGen UID: 78553).
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MLH1: Deletion/duplication analysis covers the promoter region.
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MLH1 is a member of a group of DNA mismatch repair (MMR) genes. These genes encode proteins that detect and repair DNA mismatches that can occur during cell replication. The MLH1 and PMS2 gene products interact via their C-terminal domains to form a protein complex. This complex coordinates the activities of other proteins that repair mistakes made during DNA replication. Loss of MLH1 function due to mutations causes defective DNA mismatch repair, leading to accumulation of errors in the DNA sequence as cells continue to divide, thereby increasing the risk of tumor formation.
MedGen UID: 232602
Lynch syndrome is characterized by an increased risk of colorectal cancer as well as cancers of the endometrium, ovary, prostate, stomach, small intestine, hepatobiliary tract, urinary tract, pancreas and brain (PMID: 8550246, 20533284, 23530095). Lynch syndrome tumors typically demonstrate microsatellite instability (MSI) as well as loss of expression of the mismatch repair proteins on immunohistochemical (IHC) staining. This condition is caused by pathogenic variants in one of the mismatch repair genes—MLH1, MSH2, MSH6, PMS2—as well as deletions in the 3’ end of the EPCAM gene.
The following cancer risks are associated with Lynch syndrome: colon cancer risk of up to 82% (mean age of diagnosis 44-61 years), endometrial cancer risk of up to 14-71% (mean age of diagnosis 48-62 years), gastric cancer risk of up to 13% (mean age of diagnosis 56 years), ovarian cancer risk of up to 24% (mean age of diagnosis 42.5 years). Risks for cancers of the prostate, small intestine, hepatobiliary tract, urinary tract, pancreas, and brain are also increased (PMID: 20301390, 25070057, 23530095). See the table below for gene-specific cancer risks.
|Colon||Up to 82% (PMID: 20301390, 25070057)||Up to 82% (PMID: 20301390, 25070057)||Men: up to 44%; Women: up to 20% (PMID: 20028993)||Up to 20% (PMID: 18602922)||75–82% (PMID: 21145788, 20301390)|
|Endometrial||14-54% risk (PMID: 25070057)||20–30%, up to 54% (PMID: 21642682, 23255516, 15236168)||Up to 71% (PMID: 15236168, 22619739)||Up to 15% (PMID: 25856668)||12–55% (PMID: 21145788)|
|Ovarian||Up to 20% (PMID: 25070057)||Up to 24% (PMID: 25070057)||6–8% (PMID: 23091106)||Elevated (PMID: 25856668)||Elevated (PMID: 19177550)|
|Prostate||Up to 30% (PMID: 23530095)||Up to 30% (PMID: 23530095)||Up to 30% (PMID: 23530095)||Up to 30% (PMID: 23530095, 24425144)||Up to 30% (PMID: 23530095, 24425144)|
|Gastric||Up to 13% (PMID: 20301390, 25070057)||Up to 13% (PMID: 20301390, 25070057)||Up to 13% (PMID: 25070057)||Elevated (PMID: 25856668)||Up to 13% (PMID: 20301390)|
|Duodenal||5-12% (PMID: 23408351, 25070057)||5-12% (PMID: 23408351, 25070057)||5-12% (PMID: 23408351, 25070057)||5-12% (PMID: 18602922, 23408351, 25070057)||5-12% (PMID: 23408351, 25070057)|
|Renal/urinary tract/ hepatobiliary||Up to 10% (PMID: 20301390, 15740628)||5.9% upper urinary tract; up to 25% bladder (PMID: 20591884, 23091106)||Elevated (PMID: 20591884, 15740628, 22476430, 22883484)||Elevated (PMID: 20591884)||Elevated (PMID: 20591884)|
|Sebaceous neoplasms||1-9% (PMID: 25070057, 20301390)||1-9% (PMID: 25070057, 20301390)||Unknown (PMID: 25070057)||Not reported||1-9% (PMID: 25070057, 20301390)|
|Pancreatic||Up to 4% (PMID: 19861671, 25070057)||Up to 4% (PMID: 19861671, 25070057)||Up to 4% (PMID: 19861671, 25070057)||Elevated (PMID: 19861671)||Up to 4% (PMID: 19861671, 25070057)|
|Brain/CNS||1-4% (PMID: 25070057, 20301390)||1-4% (PMID: 25070057)||1-4% (PMID: 25070057)||Elevated (PMID: 18602922)||1-4% (PMID: 25070057, 20301390)|
MLH1, MSH2, MSH6 and PMS2 are mismatch repair (MMR) genes involved in correcting mistakes incurred during DNA replication. The MSH2 and MSH6 proteins join to form a heterodimer that recognizes replication errors and initiates DNA repair. The MLH1 and PMS2 proteins also join to form a heterodimer that binds to the MSH2/MSH6 heterodimer to form a four unit complex that coordinates the activities of the other proteins involved in DNA repair. Pathogenic variants in one of the MMR genes may prevent normal mismatch repair, leading to the accumulation of errors in other genes increasing the risk of developing certain cancer types (PMID: 25070057, UniProtKB – P40692 (MLH1_HUMAN), P43246 (MSH2_HUMAN), P52701 (MSH6_HUMAN), P54278 (PMS2_HUMAN). http://www.uniprot.org/uniprot. Accessed February 2017, Genetics Home Reference. MLH1, MSH2, MSH6, PMS2. https://ghr.nlm.nih.gov/gene. Accessed February 2017).
EPCAM encodes an epithelial cellular adhesion molecule and is located upstream of MSH2 on chromosome 2. Deletions in the 3’ end of EPCAM remove a region that signals the end of the gene, which leads to the formation of a long mRNA that includes both EPCAM and MSH2. For reasons that are unclear, these 3’ deletions in EPCAM cause the MSH2 gene to be inactivated by promoter hypermethylation, leading to the loss of MSH2 expression, and similar colorectal cancer risks as those associated with MSH2 mutations. (PMID: 23264089, UniProtKB – P54278 (EPCAM_HUMAN). http://www.uniprot.org/uniprot/P16422. Accessed February 2017, Genetics Home Reference. EPCAM. https://ghr.nlm.nih.gov/gene/EPCAM. Accessed February 2017).
Lynch syndrome has autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to their offspring. Once a pathogenic mutation is detected in an individual, it is possible to identify at-risk relatives who can pursue testing for this specific familial variant. Many cases are inherited from a parent, but some can occur spontaneously (i.e., an individual with a pathogenic variant has parents who do not have it); however, that individual now has a 50% risk of passing it on to future offspring.
Additionally, individuals with a pathogenic variant in one of the MMR genes (MLH1, MSH2, MSH6, PMS2) are carriers of constitutional mismatch repair deficiency (CMMR-D). CMMR-D is a childhood-onset cancer predisposition syndrome that can present with hematological malignancies, cancers of the brain and central nervous system, Lynch syndrome-associated cancers (colon, uterine, small bowel, urinary tract), embryonic tumors, and sarcomas. Some affected individuals may also display some features of neurofibromatosis type 1—most often cafe-au-lait macules (PMID: 24737826, 24440087). For there to be a risk of CMMR-D in offspring, an individual and their partner would each have to have a single pathogenic variant in the same MMR gene; in such a case, the risk of having an affected child is 25%.
Furthermore, individuals with pathogenic variants in EPCAM are carriers of congenital tufting enteropathy (CTE). CTE is a gastrointestinal insufficiency syndrome presenting early in infancy as severe watery diarrhea. CTE is usually treated by daily nutritional supplements and occasionally, intestinal transplantation (PMID: 8057225, 18572020).
Surveillance guidelines, as published by the National Comprehensive Cancer Network® (NCCN®), suggest the following for individuals with Lynch syndrome (*NCCN. Genetic/Familial High-Risk Assessment: Colorectal. Version 2.2016):
Other extra-colonic cancers
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 as well as available genetic information that may result in a personalized plan for cancer prevention and surveillance.
It is advantageous to know if a pathogenic variant in one of the Lynch-associated genes is present as medical management recommendations can be implemented. 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 more clinically relevant data is likely to become available in the near future. Awareness of this cancer predisposition allows patients and their providers to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information, inform at-risk family members, and diligently follow condition-specific screening protocols.
*Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Genetic/Familial High-Risk Assessment: Colorectal V.2.2016. ©National Comprehensive Cancer Network, Inc 2016. All rights reserved. Accessed February 7, 2017. To view the most recent and complete version of the guideline, go online to NCCN.org. National Comprehensive Cancer Network®, NCCN®, NCCN Guidelines®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.
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|
*MLH1: Deletion/duplication analysis covers the promoter region.