• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit




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

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).

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%.

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 3.2017):

  • Colon cancer
    • Colonoscopy at age 20–25 or 2–5 years prior to the earliest colon cancer if it is diagnosed before age 25; repeat every 1–2 years.
    • There are data to suggest that aspirin may decrease the risk of colon cancer in Lynch syndrome (LS), but optimal dose and duration of aspirin therapy are unknown.
  • Other extra-colonic cancers (gastic and small bowel cancer):
    • There are no clear data to support surveillance for gastric, duodenal, and small bowel cancers in LS. Select individuals with family history of these cancers or those of Asian descent may benefit from surveillance. If surveillance is performed, may consider upper endoscopy with visualization of the duodenum at the time of colonoscopy every 3–5 years beginning at 35. Consider testing and treating H. pylori.
  • Urothelial cancer: Selected individuals such as those with family history of urothelial cancer or MSH2 mutation may want to consider screening. Surveillance options may include urinalysis starting at 30–35; however, there is insufficient evidence to recommend a surveillance strategy.
  • Central nervous system cancer: Consider annual physical/neurological examination starting at 25–30 years.
  • Pancreatic cancer: Despite data indicating an increased risk for pancreatic cancer, no effective screening techniques have been identified; therefore, there are no screening recommendations.
  • Breast cancer: There is not enough evidence to support increased screening above average-risk breast cancer screening recommendations.
  • Endometrial cancers: Women should be educated regarding prompt evaluation of abnormal uterine bleeding and post-menopausal meeting. The evaluation of these symptoms should include endometrial biopsy. Hysterectomy is a risk-reducing option that should be considered. Timing should be individualized based on when childbearing is complete, family history, comorbidities, and specific gene mutations. Screening via endometrial biopsy every 1–2 years can be considered. Transvaginal ultrasound may be considered at the physician’s discretion.
  • Ovarian cancer: Bilateral salpingo-oophorectomy is a risk-reducing option that can be considered. Timing should be individualized based on when childbearing is complete, family history, comorbidities, and specific gene mutations. Women should be educated based on the signs and symptoms of ovarian cancer (such as pelvic or abdominal pain, bloating, early satiety, or urinary frequency or urgency). Transvaginal ultrasound can be considered at clinicians discretion.
  • Reproductive options: For patients of reproductive age, advise about the risk of CMMRD (Constitutional MMR Deficiency); if both parents carry a PMS2 mutation, their offspring are at risk for CMMRD; advise about options for prenatal diagnosis.

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.

Additional reference
Referenced with permission from the NCCN Genetic/Familial High-Risk Assessment: Colorectal. Version 3.2017. © National Comprehensive Cancer Network, Inc. 2016. All rights reserved. Accessed February 2018. To view the most recent and complete version of the guideline, go online to NCCN.org.

The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available. The NCCN Guidelines® are a statement of consensus of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

Review date: February 2018

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 and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
MLH1* NM_000249.3

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