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MLH1

Alias

COCA2; FCC2; HNPCC; HNPCC2; hMLH1

Associated disorders

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).

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.

Lynch syndrome
MedGen UID: 232602

Clinical condition
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.

Gene-specific risks

Cancer MLH1 MSH2 MSH6 PMS2 EPCAM
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)

Gene information
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).

Inheritance
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).

Management
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):

Colon cancer

  • Colonoscopy every 1-2 years starting at 20-25 years of age, or 2-5 years prior to the earliest colon cancer if diagnosed before age 25.

Gynecological cancers

  • Prophylactic hysterectomy and bilateral salpingo-oophorectomy (BSO) may be considered by women after childbearing is complete.
    • Education regarding prompt evaluation for dysfunctional uterine bleeding
  • There is no clear evidence to support routine endometrial cancer screening, nor do the data support ovarian cancer screening; however:
    • Annual office endometrial sampling is an option.
    • Serum CA-125 for ovarian cancer and transvaginal ultrasound for ovarian and endometrial cancer may be considered at the clinician’s discretion. These modalities have not been shown to be sufficiently sensitive or specific to support a positive recommendation.

Other extra-colonic cancers

  • While there is no clear evidence to support screening for gastric, duodenal, and small bowel cancer, select individuals, families, or those of Asian descent may consider esophagogastroduodenoscopy (EGD) with extended duodenoscopy every 3-5 years beginning at age 30-35 years of age.
    • Consider testing for and treating H. pylori.
  • Consider annual urinalysis beginning at 30-35 years of age to screen for urothelial cancer.
  • Consider annual physical/neurologic examination starting at 25-30 years of age.
  • NCCN® states that no screening recommendation can be made for pancreatic cancer at this time (*NCCN. Genetic/Familial High-Risk Assessment: Colorectal. Version 2.2016). In contrast, the American College of Gastroenterology Clinical Guidelines recommend pancreatic cancer screening for individuals with Lynch syndrome with a first- or second-degree relative affected with pancreatic cancer (PMID: 25645574, 23135763). Ideally, screening should be performed in experienced centers utilizing a multidisciplinary approach under research conditions. Recommended screening includes annual endoscopic ultrasound and/or MRI of the pancreas starting at age 50 or 10 years younger than the earliest age of pancreatic cancer diagnosis in the family (PMID: 25645574).

Other considerations

  • Referral for genetic counseling, inclusive of a discussion regarding recurrence risks for both autosomal dominant and recessive conditions associated with pathogenic variants in MLH1, PMS2, MSH2, MSH6, and EPCAM.

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.

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
MLH1* NM_000249.3


*MLH1: Deletion/duplication analysis covers the promoter region.