MLH1 gene

Associated Syndrome Name: Lynch syndrome/Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

MLH1 Summary Cancer Risk Table

Cancer Genetic Cancer Risk
ColorectalHigh Risk
EndometrialHigh Risk
GastricHigh Risk
OtherHigh Risk
OvarianHigh Risk
SkinHigh Risk
PancreaticElevated Risk
ProstateElevated Risk

MLH1 gene Overview

Lynch syndrome 1, 2, 3, 4, 5, 6, 7, 8, 9, 10
  • Individuals with mutations in MLH1 have Lynch syndrome. This condition is also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC).
  • Men and women with Lynch syndrome due to mutations in MLH1 have a high risk of developing colorectal cancer, often at young ages. Colorectal cancer in patients with Lynch syndrome develops from adenomatous polyps which progress to cancer more quickly than polyps in individuals who do not have Lynch syndrome.
  • Women with Lynch syndrome due to mutations in MLH1 have a high risk for developing endometrial and ovarian cancer, often at young ages.
  • Patients with Lynch syndrome due to mutations in MLH1 also have an increased risk of developing a wide variety of other cancers, including small bowel, urinary tract, hepatobiliary tract, brain (usually glioblastoma), sebaceous gland, prostate and pancreatic. These risks may be more significant in patients with a family history of these cancers. Therefore, the general screening and management recommendations provided below should be modified based on individualized risk assessment and counseling.
  • Patients with Lynch syndrome due to mutations in MLH1 have an increased risk for gastric cancer. Screening may be particularly important for patients with additional risk factors for gastric cancer, such as being male, older age, first-degree relative with gastric cancer, Asian ethnicity, residing in, or immigrating from countries with high background incidence of gastric cancer, chronic autoimmune gastritis, gastric intestinal metaplasia, and gastric adenomas.
  • Studies have investigated the possibility that patients with Lynch syndrome have an increased risk for other cancers, including breast cancer and adrenocortical carcinoma. However, the data are not conclusive at this time and there are currently no medical management guidelines related to these cancers.
  • Patients with Lynch syndrome have a high risk for developing second primary cancers following an initial diagnosis of colorectal or endometrial cancer. This includes a high risk for endometrial cancer in women following colorectal cancer and vice versa, a high risk for a second primary colorectal cancer in any portions of the colon or rectum remaining after surgical treatment, and a high risk for other Lynch associated cancers, such as those of the upper gastrointestinal tract, urinary tract, and other sites.
  • Although there are high risks for cancer in patients with Lynch syndrome, many of these risks can be greatly reduced with appropriate medical management. Guidelines for the medical management of patients with Lynch syndrome have been developed by the National Comprehensive Cancer Network (NCCN) and other expert groups. These are listed below. It is recommended that patients with an MLH1 mutation and a diagnosis of Lynch syndrome be managed by a multidisciplinary team with expertise in medical genetics and the care of patients with this condition.

MLH1 gene Cancer Risk Table

Cancer Type Age Range Cancer Risk Risk for General Population
ColorectalTo age 701, 2, 11, 12, 13, 1440%-58%1.8%
EndometrialTo age 701, 2, 11, 12, 13, 14, 1529%-54%1.9%
Overall cancer risk (Lynch cancers)Risk for a second Lynch-related cancer after a first cancer diagnosis16, 17Increased riskNA
OvarianTo age 701, 2, 11, 12, 13, 14, 155%-20%0.6%
GastricTo age 7012, 13, 14, 156%-11%0.3%
Small BowelTo age 7012, 13, 14, 154%-5%0.1%
UrothelialTo age 701, 9, 12, 14, 182%-7%0.7%
PancreaticTo age 7010, 12, 14Up to 4%0.6%
BrainTo age 702, 12, 13, 14, 15Up to 2%0.4%
ProstateTo age 702, 12, 147%-13%6.1%
Hepatobiliary TractTo age 7011, 12, 13, 142%-4%0.5%
Lynch-associated Skin TumorsTo age 703, 71%-9%<1.0%

MLH1 Cancer Risk Management Table

The overview of medical management options provided is a summary of professional society guidelines. The most recent version of each guideline should be consulted for more detailed and up-to-date information before developing a treatment plan for a particular patient.

This overview is provided for informational purposes only and does not constitute a recommendation. While the medical society guidelines summarized herein provide important and useful information, medical management decisions for any particular patient should be made in consultation between that patient and his or her healthcare provider and may differ from society guidelines based on a complete understanding of the patient’s personal medical history, surgeries and other treatments.

Cancer Type Procedure Age to Begin Frequency
(Unless otherwise indicated by findings)
ColorectalColonoscopy320 to 25 years, or 2 to 5 years younger than the earliest colorectal cancer diagnosis in family if it is under age 25Every 1 to 2 years
Consider the use of aspirin as a risk-reduction agent3IndividualizedIndividualized
EndometrialPatient education about the importance of quickly seeking attention for endometrial cancer symptoms, such as abnormal bleeding or menstrual cycle irregularities3IndividualizedIndividualized
Consider pelvic examination, endometrial sampling and transvaginal ultrasound.330 to 35 yearsEvery 1 to 2 years
Consider hysterectomy.3After completion of childbearingNA
OvarianConsider bilateral salpingo-oophorectomy.3After completion of childbearingNA
Consider transvaginal ultrasound and CA-125 measurement.330 to 35 yearsNA
Consider options for ovarian cancer risk-reduction agents (i.e. oral contraceptives).3, 20IndividualizedNA
Patient education about ovarian cancer symptoms3IndividualizedNA
GastricConsider testing and treating Helicobacter pylori infection.3IndividualizedNA
Consider upper endoscopy, particularly for patients with additional risk factors (see clinical overview). Consider biopsy of the proximal and distal stomach.3, 2240 yearsEvery 3 to 5 years
Small BowelConsider upper endoscopy, particularly for patients with additional risk factors for small bowel cancer, such as family history.330 to 40 yearsEvery 3 to 5 years
UrothelialConsider urinalysis.330 to 35 yearsAnnually
PancreaticFor patients with a family history of pancreatic cancer, consider available options for pancreatic cancer screening, including the possibility of endoscopic ultrasonography (EUS) and MRI/magnetic resonance cholangiopancreatography (MRCP). It is recommended that patients who are candidates for pancreatic cancer screening be managed by a multidisciplinary team with experience in screening for pancreatic cancer, preferably within research protocols.3, 2145 to 50 years, or 10 years younger than the earliest diagnosis of pancreatic cancer in the familyAnnually
Provide education about ways to reduce pancreatic cancer risk, such as not smoking and losing weight.23IndividualizedIndividualized
BrainPatient education about the importance of quickly seeking attention for signs and symptoms of neurologic cancer3IndividualizedNA
ProstateIncorporating information about increased risk due to gene mutation, start risk and benefit discussion about offering baseline digital rectal examination (DRE) and Prostate Specific Antigen (PSA).3, 24Age 40Individualized, consider annually
Hepatobiliary TractCurrently there are no specific medical management guidelines for hepatobiliary cancer risk in mutation carriers.3NANA
Lynch-associated Skin TumorsConsider skin exams3IndividualizedEvery 1 to 2 years
For Patients With A Cancer DiagnosisFor patients with a gene mutation and a diagnosis of cancer, targeted therapies may be available as a treatment option for certain tumor types (e.g., antibodies to PD-1)19NANA

Information for Family Members

The following information for Family Members will appear as part of the MMT for a patient found to have a mutation in the MLH1 gene.

This patient's relatives are at risk for carrying the same mutation(s) and associated cancer risks as this patient. Cancer risks for females and males who have this/these mutation(s) are provided below.

Family members should talk to a healthcare provider about genetic testing. Close relatives such as parents, children, brothers and sisters have the highest chance of having the same mutation(s) as this patient. Other more distant relatives such as cousins, aunts, uncles, and grandparents also have a chance of carrying the same mutation(s). Testing of at-risk relatives can identify those family members with the same mutation(s) who may benefit from surveillance and early intervention.

In rare instances, an individual may inherit mutations in both copies of the MLH1 gene, leading to the condition Constitutional Mismatch Repair-Deficiency syndrome (CMMR-D). Individuals with CMMR-D often have significant complications in childhood, including colorectal polyposis and a high risk for colorectal, small bowel, brain, and hematologic cancers. Individuals with CMMR-D often have café-au-lait spots. The children of this patient are at risk of inheriting CMMR-D only if the other parent is also a carrier of a MLH1 mutation. Screening the other biological parent of any children for MLH1 mutations may be appropriate.7

Parents who are concerned about the possibility of passing on an MLH1 mutation to a future child may want to discuss options for prenatal testing and assisted reproduction techniques, such as pre-implantation genetic diagnosis (PGD).3

References

  1. Møller P, et al. Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database. Gut. 2017 66:464-472. PMID: 26657901.
  2. Dominguez-Valentin M, et al. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genet Med. 2020 22:15-25. PMID: 31337882.
  3. Gupta S, et al. NCCN Clinical Practice Guidelines in Oncology® Genetic/Familial High-Risk Assessment: Colorectal. V 1.2021. May 11. Available at https://www.nccn.org.
  4. Ryan S, et al. Risk of prostate cancer in Lynch syndrome: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev. 2014 23:437-49. PMID: 24425144.
  5. Grindedal EM, et al. Germ-line mutations in mismatch repair genes associated with prostate cancer. Cancer Epidemiol Biomarkers Prev. 2009 18:2460-7. PMID: 19723918.
  6. Raymond VM, et al. Elevated risk of prostate cancer among men with Lynch syndrome. J Clin Oncol. 2013 31:1713-8. oi: 10.1200/JCO.2012.44.1238. Epub 2013 Mar 25. PMID: 23530095.
  7. Kohlmann W, Gruber SB. Lynch Syndrome. 2018 Apr 12. In:Pagon RA, et al., editors. GeneReviews® [Internet]. PMID: 20301390.
  8. Lin KM, et al. Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population. Dis Colon Rectum. 1998 41:428-33. PMID: 9559626.
  9. Joost P, et al. Urinary Tract Cancer in Lynch Syndrome; Increased Risk in Carriers of MSH2 Mutations. Urology. 2015 86:1212-7. PMID: 26385421.
  10. Kastrinos F, et al. Risk of pancreatic cancer in families with Lynch syndrome. JAMA. 2009 302:1790-5. PMID: 19861671.
  11. Bonadona V, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011 305:2304-10. PMID: 21642682.
  12. Møller P, et al. Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database. Gut. 2018 67:1306-1316. PMID: 28754778.
  13. Barrow E, et al. Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations. Clin Genet. 2009 75:141-9. PMID: 19215248.
  14. SEER*Explorer: An interactive website for SEER cancer statistics [Internet]. Surveillance Research Program, National Cancer Institute. [Cited 2020 Sep 14]. Available from https://seer.cancer.gov/explorer/.
  15. Vasen HF, et al. Hereditary cancer registries improve the care of patients with a genetic predisposition to cancer: contributions from the Dutch Lynch syndrome registry. Fam Cancer. 2016 15:429-35. PMID: 26973060.
  16. Win AK, et al. Risks of colorectal and other cancers after endometrial cancer for women with Lynch syndrome. J Natl Cancer Inst. 2013 105:274-9. PMID: 23385444.
  17. Win AK, et al. Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. J Natl Cancer Inst. 2012 104:1363-72. PMID: 22933731.
  18. Skeldon SC, et al. Patients with Lynch syndrome mismatch repair gene mutations are at higher risk for not only upper tract urothelial cancer but also bladder cancer. Eur Urol. 2013 63:379-85. PMID: 22883484.
  19. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s031lbl.pdf
  20. Daly M et al. NCCN Clinical Practice Guidelines in Oncology®: Genetic/Familial High-Risk Assessment: Breast, Ovarian and Pancreatic. V 1.2022. Aug 11. Available at https://www.nccn.org.
  21. Goggins M, et al. Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. Gut. 2020 69:7-17. PMID: 31672839.
  22. Ajani JA, et al. NCCN Clinical Practice Guidelines in Oncology®: Gastric Cancer. V 4.2021. Aug 3. Available at https://www.nccn.org.
  23. Tempero MA, et al. NCCN Clinical Practice Guidelines in Oncology®: Pancreatic Adenocarcinoma. V 2.2021. Feb 25. Available at https://www.nccn.org.
  24. Carroll PR, et al. NCCN Clinical Practice Guidelines in Oncology®: Prostate Cancer Early Detection. V 2.2021. July 14. Available at https://www.nccn.org.
Last Updated on 21-Apr-2022