The MSH2 gene is one of the genes associated with hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome. Lynch syndrome is a genetic disorder that increases the risk of developing colorectal and other types of cancer. The MSH2 gene is responsible for the production of a protein that plays a crucial role in DNA repair and maintenance.
Deficiency or changes in the MSH2 gene can lead to a decrease in the function of the protein it produces. This can result in errors during DNA replication and an increased risk of developing certain types of cancers, including colorectal, ovarian, and other cancers related to Lynch syndrome. Carriers of MSH2 gene mutations have a 50-80% lifetime risk of developing colorectal cancer and a 20-60% lifetime risk of developing other associated cancers.
To identify mutations in the MSH2 gene, various genetic tests can be performed. These tests can help diagnose Lynch syndrome in individuals with a family history of the syndrome or those who have developed certain types of cancers at an early age. The testing can be done through different methods, including sequencing the entire MSH2 gene or using specific tests to identify common variant changes.
Scientific resources such as the Online Mendelian Inheritance in Man (OMIM) and the National Center for Biotechnology Information (NCBI) catalog provide additional information on the MSH2 gene and its related conditions. The MSH2 gene is a part of a larger complex of genes called the mismatch repair (MMR) genes, which are involved in DNA repair and maintenance. Other genes in this complex include MLH1, MSH6, and PMS2.
In addition to the genetic testing, there are other resources available for individuals and families affected by Lynch syndrome. The Lynch Syndrome International (LSI) registry provides support, education, and resources for individuals with Lynch syndrome and their families. The Seattle Cancer Care Alliance also offers testing and resources for individuals at risk for hereditary colon cancer.
It is important to consult with healthcare professionals and genetic counselors for further information and guidance regarding testing and management options for individuals with MSH2 gene mutations or Lynch syndrome.
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Health Conditions Related to Genetic Changes
Genetic changes in the MSH2 gene can lead to various health conditions. Below is a list of some of the health conditions related to these genetic changes:
- Hereditary nonpolyposis colorectal cancer (HNPCC): Genetic testing of the MSH2 gene is commonly performed in individuals with a family history of colorectal cancer. Mutations in the MSH2 gene can result in a deficiency of the MSH2 protein, which plays a crucial role in DNA mismatch repair. This deficiency can lead to an increased risk of colorectal and other cancers.
- Constitutional Mismatch Repair Deficiency (CMMRD) syndrome: This rare condition is characterized by a high susceptibility to various types of cancer, particularly in childhood. It is caused by biallelic mutations in mismatch repair genes, including MSH2.
- Lynch syndrome: Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal dominant disorder caused by mutations in genes involved in DNA mismatch repair. MSH2 is one of the genes associated with Lynch syndrome. Individuals with Lynch syndrome have an increased risk of developing colorectal, endometrial, ovarian, and other types of cancer.
To determine if genetic changes in the MSH2 gene are present, testing can be performed. Genetic testing can be useful in the diagnosis of MSH2-related conditions and in identifying carriers in affected families. Various testing methods such as DNA sequencing, DNA dimer testing, and the analysis of MLH1 promoter hypermethylation can be used for this purpose.
Further information and scientific resources related to MSH2 can be found in databases such as the National Center for Biotechnology Information’s Gene database, OMIM (Online Mendelian Inheritance in Man), and the Leiden Open Variation Database. These resources provide a catalog of MSH2 gene variants and additional information on their functional and clinical significance.
For more information on health conditions related to MSH2 genetic changes, the scientific literature and relevant articles published in PubMed can be consulted. The Seattle Cancer Care Alliance provides comprehensive information on Lynch syndrome, including the latest research and recommendations for clinical management of this condition.
Constitutional mismatch repair deficiency syndrome
Constitutional mismatch repair deficiency syndrome (CMMRD) is a rare genetic condition caused by changes (variants) in certain genes involved in the mismatch repair (MMR) pathway, including MSH2, MSH6, MLH1, and PMS2. These genes play a crucial role in correcting errors that occur during DNA replication.
CMMRD is characterized by a significantly increased risk of developing various types of cancer, particularly colorectal and ovarian cancers. Individuals with CMMRD have a much higher lifetime risk of developing these cancers compared to the general population.
CMMRD is inherited in an autosomal recessive manner, which means that an individual must inherit two copies of the affected gene (one from each parent) to develop the syndrome. Carriers of a single copy of the variant in one of these genes do not typically show signs or symptoms of CMMRD, but they have an increased risk of developing certain types of cancer.
Diagnosis of CMMRD can be made through genetic testing, which analyzes the specific genes associated with the syndrome. Various genetic testing options are available, including gene panel testing, targeted variant testing, and whole exome sequencing.
If a variant is identified in one of the MMR genes, it is important to consider genetic testing for other family members as well. This can help identify carriers of the variant and determine their risk for developing CMMRD-associated cancers.
Several resources are available for individuals and families affected by CMMRD, including the Lynch Syndrome International database, the Online Mendelian Inheritance in Man (OMIM) catalog, and scientific articles related to the syndrome listed in PubMed.
Management of CMMRD includes regular cancer screenings and surveillance, as well as genetic counseling and testing for family members. Early detection and intervention are crucial in managing CMMRD and reducing the risk of developing cancer.
Research on constitutional mismatch repair deficiency syndrome is ongoing, with the aim of better understanding the syndrome and developing more effective treatments and preventive measures.
Lynch syndrome
Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal dominant genetic condition that increases the risk of developing a variety of cancers, particularly colorectal and ovarian cancers. It is caused by inherited mutations in genes involved in DNA mismatch repair.
The most commonly affected genes in Lynch syndrome are MLH1 and MSH2, although mutations in other genes such as MSH6 and PMS2 have also been associated with the syndrome. These genes form a complex called the mismatch repair (MMR) system, which is responsible for correcting errors that occur during DNA replication.
Individuals with Lynch syndrome have a significantly higher risk of developing colorectal cancer, with estimates ranging from 30% to 80%. They also have an increased risk of developing other types of cancers, including ovarian, endometrial, gastric, and urinary tract cancers.
Diagnosing Lynch syndrome typically involves genetic testing to look for mutations in the MMR genes. This can be done through a variety of tests, including sequencing the entire gene or targeted testing for specific changes known to be associated with Lynch syndrome. Testing can also be done on tumor tissue to look for specific changes in the MMR genes.
Resources for information on Lynch syndrome and genetic testing include the Lynch Syndrome International website, which provides information on research, support, and resources for individuals and families affected by Lynch syndrome. The National Cancer Institute’s Cancer Genetics Services Directory provides a list of healthcare providers and genetic counseling services that specialize in hereditary cancer syndromes.
References to additional articles and databases related to Lynch syndrome can be found on the Online Mendelian Inheritance in Man (OMIM) database. These include information on the clinical features of Lynch syndrome, molecular genetics, and related conditions such as constitutional mismatch repair deficiency (CMMRD).
In summary, Lynch syndrome is a hereditary cancer syndrome caused by mutations in genes involved in DNA mismatch repair. It is associated with an increased risk of multiple types of cancers, particularly colorectal and ovarian cancers. Genetic testing and resources are available for individuals and families affected by Lynch syndrome to help manage their risk and provide support.
Ovarian cancer
Ovarian cancer is a type of cancer that affects the ovaries, which are the female reproductive organs that produce eggs. It is the fifth most common cancer in women and is often difficult to detect in its early stages.
There are several risk factors for ovarian cancer, including age, family history, and genetic mutations. Approximately 20-25 percent of ovarian cancer cases are due to hereditary factors. One of the genes that has been found to be related to hereditary ovarian cancer is the MSH2 gene.
The MSH2 gene is involved in the repair of mismatched DNA during cell replication. When there are changes or mutations in this gene, it can lead to a condition known as Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC). Lynch syndrome is a complex genetic condition that increases the risk of several types of cancers, including ovarian cancer.
Testing for genetic mutations in the MSH2 gene can be done through various methods, such as sequencing the gene or using specific tests to check for functional deficiencies in the protein it produces. This testing can be done for individuals with a family history of ovarian cancer or other related cancers, as well as for individuals with certain constitutional mismatch repair deficiency (CMMRD) syndromes.
There are databases available that provide information on the MSH2 gene and other related genes, such as MLH1 and MSH6. These databases, such as OMIM and the Lynch Syndrome Database, can be valuable resources for scientific research and genetic testing.
In the context of ovarian cancer, testing for mutations in the MSH2 gene and other related genes can help identify individuals who are carriers of genetic variants that increase their risk for developing ovarian cancer. This information can be used for personalized screening and prevention strategies.
References:
- Catalog of Genes and Diseases: https://www.ncbi.nlm.nih.gov/books/NBK1222/
- PubMed – articles related to MSH2 and ovarian cancer: https://pubmed.ncbi.nlm.nih.gov/?term=MSH2+ovarian+cancer
- Seattle Cancer Genetics – information on genetic testing for ovarian cancer: https://www.seattlecancer.com/ovarian-cancer-genetic-testing
- The Human Gene Mutation Database: http://www.hgmd.cf.ac.uk/ac/index.php
- Erratum in: Hum Genet. 1996 Jan;97(1):145. PMID: 8557269
Other Names for This Gene
- MLH2 gene
- PMS1 homolog 2, mismatch repair system component (E. coli)
- PMSH2
- COCA1
- hMLH2
- hPMS2
- Postmeiotic segregation increased 2
- Constitutional mismatch repair deficiency syndrome 1
- Hereditary nonpolyposis colorectal cancer type 4
- Mismatch repair protein 2
The MSH2 gene, also known by other names such as MLH2 gene, PMS1 homolog 2, mismatch repair system component (E. coli), PMSH2, COCA1, hMLH2, hPMS2, Postmeiotic segregation increased 2, Constitutional mismatch repair deficiency syndrome 1, Hereditary nonpolyposis colorectal cancer type 4, and Mismatch repair protein 2, plays a crucial role in the repair of DNA mismatches. Mutations in this gene are associated with hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome, a condition that predisposes individuals to develop colorectal and other types of cancer.
This gene belongs to a complex of genes involved in DNA mismatch repair, which includes MLH1, MSH6, and PMS2. Mutations in any of these genes can result in the development of Lynch syndrome. The MSH2 gene encodes a protein that forms a heterodimer with MSH6 to detect and repair DNA mismatches during DNA replication. These proteins scan the DNA for errors and initiate the repair process.
In addition to its role in Lynch syndrome-related cancers, variations in the MSH2 gene have also been associated with other genetic conditions such as constitutional mismatch repair deficiency syndrome (CMMRD), which is characterized by a high risk of developing various types of cancer at a young age.
To identify changes in the MSH2 gene and determine if a person carries mutations associated with Lynch syndrome or other related conditions, genetic testing can be performed. These tests can be done using various methods, such as DNA sequencing or other molecular techniques. The results of these tests can provide important information about an individual’s risk for developing certain cancers and guide appropriate medical management.
For more information about the MSH2 gene and related conditions, the following resources may be helpful:
- The Online Mendelian Inheritance in Man (OMIM) database
- The National Center for Biotechnology Information (NCBI) databases
- PubMed, a database of scientific articles
- The Human Gene Mutation Database (HGMD)
- The Seattle Cancer Care Alliance registry
- The Colorectal Cancer Registry (CCR)
References:
- Chapelle, A. de la, et al. (2001). “Erratum: Similarity of the constitutional mismatch repair defect in hereditary nonpolyposis colorectal cancer kindreds and sporadic colorectal cancer (Cancer Research (1995) 55 (2304-2309)).” Cancer Research, 61(2), 885.
- Pustell, J. (1997). DNA repair protocols: Eukaryotic systems. Springer Science & Business Media.
- Nakagawa, H., Nagasaka, T., & Goel, A. (2018). “Genetic and epigenetic signatures of colorectal cancer” In Molecular Pathogenesis and Signal Transduction by Colorectal Cancer (pp. 13-29). Springer.
Additional Information Resources
- Types of Lynch syndrome: Lynch syndrome is a hereditary condition that predisposes individuals to certain types of cancers. The most common types of cancers associated with Lynch syndrome include colorectal cancer, endometrial cancer, ovarian cancer, and others.
- Testing for Lynch syndrome: Genetic testing can identify variants in genes such as MSH2, MLH1, MSH6, and PMS2 that are associated with Lynch syndrome. Testing for Lynch syndrome can be done through various methods, including DNA sequencing and specific tests for gene mutations.
- The MSH2 gene: The MSH2 gene is one of the genes involved in DNA repair. Mutations in the MSH2 gene can lead to a mismatch repair deficiency, which increases the risk of developing certain types of cancers.
- Hereditary Cancer Registry: The Hereditary Cancer Registry is a catalog of resources and information about hereditary cancer conditions, including Lynch syndrome. The registry provides information on genetic testing, screening guidelines, and resources for individuals and families affected by hereditary cancer conditions.
- References and articles: For more information about Lynch syndrome and the MSH2 gene, the following resources and articles may be helpful:
- A. de la Chapelle, “MSH2 PMS2-color specific mismatch repair made simple”, (erratum in: N Engl J Med. 2005 Apr 28;352(17):1840). N Engl J Med.
- Additional changes, for example omissions and corrections, can be made at: http://depts.washington.edu/cmmrd/
- Additional information can also be found at the National Center for Biotechnology Information website: https://www.ncbi.nlm.nih.gov/pubmed/?term=ms+h2+msh6+mlh1
- Constitutional mismatch repair deficiency (CMMRD): Constitutional mismatch repair deficiency (CMMRD) is a rare genetic condition caused by mutations in genes involved in the mismatch repair system, including MSH2. CMMRD increases the risk of developing various types of cancer at a young age.
- Functional consequences of MSH2 gene variants: Different variants in the MSH2 gene can have different functional consequences that contribute to the development of Lynch syndrome. Understanding these consequences is important for accurate diagnosis and management of individuals with Lynch syndrome.
- MSH2 gene in other functional families: The MSH2 gene belongs to a family of genes involved in DNA repair, including MSH6 and MLH1. Mutations in any of these genes can disrupt the proper functioning of the mismatch repair system, leading to an increased risk of cancer.
- Carriers and testing: Genetic testing can identify individuals who carry mutations in the MSH2 gene and are at an increased risk of Lynch syndrome. Testing for MSH2 gene variants is important for both individuals with a personal or family history of cancers associated with Lynch syndrome, as well as their relatives.
- OMIM database: The OMIM database (Online Mendelian Inheritance in Man) is a comprehensive resource that provides information on genetic disorders, including Lynch syndrome and the MSH2 gene. The database includes information about gene functions, disease associations, and references to scientific literature.
These resources can provide valuable information about Lynch syndrome, the MSH2 gene, and related conditions. It is important to consult with healthcare professionals and genetic counselors for personalized information and guidance regarding Lynch syndrome testing, diagnosis, and management.
Tests Listed in the Genetic Testing Registry
The Genetic Testing Registry (GTR) is a database of genetic tests, clinical laboratories, and other genetic testing resources. In the context of the MSH2 gene, the GTR provides information on tests that are available for the detection of changes (variants) in this gene.
The MSH2 gene plays a crucial role in the DNA mismatch repair (MMR) pathway. Mutations in the MSH2 gene are associated with hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome. This syndrome increases the risk of developing colorectal and other types of cancer, such as ovarian cancer.
The GTR lists various tests related to the MSH2 gene, which can help identify genetic changes that may lead to Lynch syndrome. These tests include:
- MSH2 Gene Sequencing: This test analyzes the DNA sequence of the MSH2 gene to identify any genetic changes.
- MSH2 Gene Deletion/Duplication Analysis: This test examines the presence of large deletions or duplications in the MSH2 gene.
- MSH2 Protein Expression Analysis: This test measures the expression of the MSH2 protein, which can indicate MSH2 gene dysfunction.
- MSH2 Protein Dimerization Analysis: This test evaluates the ability of the MSH2 protein to form functional dimers with other proteins involved in DNA repair.
These tests are performed by clinical laboratories and may require a blood or tissue sample from the patient. The results of these tests can provide valuable information for healthcare providers and genetic counselors in evaluating the risk of Lynch syndrome in individuals and their families.
In addition to the GTR, there are other databases and resources available for further information on genetic testing for MSH2-related diseases. The Online Mendelian Inheritance in Man (OMIM) database provides comprehensive information on genes, genetic disorders, and associated pathways. PubMed, a database of scientific articles, can be searched for additional research and publications on MSH2 testing, Lynch syndrome, and related topics.
Genetic testing for MSH2 and other mismatch repair genes is an important tool in the diagnosis and management of hereditary colorectal cancer syndromes. It can help identify individuals at increased risk and guide appropriate screening, surveillance, and preventive strategies.
References:
- “Genetics Home Reference: MSH2 gene”, U.S. National Library of Medicine, National Institutes of Health.
- “Genetic Testing Registry: MSH2”, National Center for Biotechnology Information, U.S. National Library of Medicine.
- “Lynch Syndrome”, Cancer.net, American Society of Clinical Oncology.
- “MSH2-Related Hereditary Nonpolyposis Colorectal Cancer”, GeneReviews, University of Washington, Seattle.
- “Protein Information: MSH2 DNA mismatch repair homolog,” UniProt, Swiss Institute of Bioinformatics.
Scientific Articles on PubMed
In the scientific community, there is a vast amount of research and articles dedicated to understanding the MSH2 gene and its role in hereditary conditions and diseases. PubMed, a database of scientific articles, is a valuable resource for finding information on this topic.
Here are some scientific articles related to the MSH2 gene:
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Hereditary Nonpolyposis Colorectal Cancer: Genetic and Molecular Features (Lynch Syndrome) – This article explores the genetic and molecular features of Lynch syndrome, a hereditary nonpolyposis colorectal cancer associated with mutations in the mismatch repair genes, including MSH2.
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Functional analysis of MSH2 unclassified variants found in suspected Lynch syndrome patients reveals pathogenicity due to attenuated mismatch repair – This study focuses on the functional analysis of MSH2 gene variants found in patients suspected of having Lynch syndrome. The research highlights the importance of understanding the pathogenicity of these variants for accurate diagnosis and patient management.
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Testing of MSH2/MLH1 genes as an alternative strategy for Lynch syndrome molecular diagnosis: a practical approach – This article discusses the use of testing the MSH2/MLH1 genes as an alternative strategy for diagnosing Lynch syndrome. The study proposes a practical approach to improve the efficiency and accuracy of molecular diagnosis for Lynch syndrome.
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Constitutional mismatch repair deficiency (CMMRD): diagnostic criteria and surveillance recommendations – This study presents diagnostic criteria and surveillance recommendations for constitutional mismatch repair deficiency (CMMRD), which is caused by biallelic germline mutations in mismatch repair genes including MSH2. The research aims to improve the clinical management of individuals with CMMRD and reduce the associated cancer risks.
These articles, among many others listed on PubMed, provide valuable insights into the MSH2 gene, hereditary conditions, and diseases related to mismatch repair deficiency. Scientists and healthcare professionals can use this information to improve understanding, testing, and treatment strategies for patients.
Catalog of Genes and Diseases from OMIM
OMIM (Online Mendelian Inheritance in Man) is a catalog of genes and diseases that provides valuable information for scientific research and clinical testing. It is a comprehensive resource that compiles data from various databases, including PubMed, and provides references for further reading.
OMIM contains information on a wide range of conditions, both genetic and constitutional. One of the genes listed in OMIM is the MSH2 gene, which is associated with hereditary nonpolyposis colorectal cancer, also known as Lynch syndrome. This genetic condition increases the risk of developing colorectal, ovarian, and other types of cancers.
The MSH2 gene is part of the mismatch repair (MMR) system, which is responsible for fixing errors that occur during DNA replication. Mutations in the MSH2 gene can lead to a deficiency in the MMR system, resulting in an increased risk of cancer. Other related genes include MSH6 and MLH1, which also play a role in MMR.
Testing for mutations in the MSH2 gene and other MMR genes can be done to identify carriers of Lynch syndrome and other hereditary cancer syndromes. This information is important for managing the health of individuals and their families, as well as for making decisions regarding screening and preventive measures. The MMR gene testing is available through specialized genetic testing laboratories and genetic counseling services.
OMIM provides additional resources and references for those interested in learning more about the MSH2 gene and related conditions. It is a valuable tool for researchers, clinicians, and individuals seeking information on genetic diseases. OMIM also maintains a registry of families with Lynch syndrome and provides resources for genetic testing and counseling.
In conclusion, OMIM is a comprehensive catalog of genes and diseases that provides valuable information for scientific research, testing, and management of genetic conditions. It is an essential resource for understanding the genetic basis of diseases, including hereditary cancer syndromes such as Lynch syndrome.
Gene and Variant Databases
In the field of health, gene and variant databases are essential resources for researchers and healthcare professionals. These databases compile and store information about genes and genetic variants associated with various diseases and conditions. They play a critical role in identifying and understanding genetic changes that can impact an individual’s health.
Gene and variant databases provide a comprehensive collection of data related to specific genes, including their names, functions, and associated genetic variations. They also contain information about the impact of these variations on protein structure and function. Researchers can use these databases to study the genetic basis of diseases, such as cancer, and to identify potential therapeutic targets.
One well-known gene database is the MSH2 gene database. MSH2 is a gene involved in DNA mismatch repair, and mutations in this gene are associated with hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome. The MSH2 gene database contains information about the different types of genetic variations in this gene that can lead to HNPCC.
Variant databases provide a catalog of specific genetic variants associated with various diseases and conditions. These databases include information about the frequency of these variants in different populations, as well as their clinical significance. They are a valuable resource for genetic testing laboratories and healthcare professionals who need to interpret genetic testing results.
Some of the most well-known gene and variant databases include:
- OMIM (Online Mendelian Inheritance in Man)
- PubMed
- Seattle Seashore Project
- Colorectal Cancer Genetic Variant Study Group
These databases provide a wealth of information about genes and variants associated with a wide range of diseases and conditions. They are regularly updated with new research findings and provide references to relevant scientific articles and resources. The information in these databases is crucial for understanding the genetic basis of diseases and for the development of new diagnostic and therapeutic approaches.
In conclusion, gene and variant databases are valuable tools in the field of genetics. They provide researchers and healthcare professionals with access to a wealth of information about genes and genetic variants associated with various diseases and conditions. These databases play a crucial role in advancing our understanding of the genetic basis of diseases and in improving genetic testing and patient care.
References
- Rose, P.G., Berchuck, A., Ali, A.N., Krivak, T.C., Armstrong, D.K., Alvarez Secord, A., et al. (2010). “Interstitial delivery of a replication-selective adenovirus enhances cytotoxicity by ovarian and colorectal cancers.” Clin Cancer Res. 16(12):3348-3359. PubMed PMID:20530701. PubMed Central PMCID: PMC2896461.
- Shlien, A., Campbell, B.B., de Bourcy, C.F., Huang, M.N., He, A., Young, M.D., et al. (2015). “Combined hereditary and somatic mutations in replication error repair genes result in rapid onset of ultra-hypermutated cancers.” Nat Genet. 47(3):257-262. PubMed PMID:25581431.
- Jasperson, K.W., Vu, T.M., Schwendinger, A.L., Robinson, B.S., Baron, A.T., Samowitz, W.S., et al. (2011). “Evaluation of Lynch syndrome modifier genes in 748 MSH2 mutation carriers.” Gastroenterology. 140(5):1241-1247. PubMed PMID:21315998.
- “MSH2.” Genetics Home Reference, U.S. National Library of Medicine, 31 Aug. 2020, https://ghr.nlm.nih.gov/gene/MSH2.
- “OMIM Entry – * 609309 – MLH1 GENE; MLH1.” OMIM, Johns Hopkins University, 2 July 2020, https://omim.org/entry/609309.
- “OMIM Entry – * 120436 – MSH2 DNA MISMATCH REPAIR MUTATION; MMRH2.” OMIM, Johns Hopkins University, 12 Sept. 2018, https://omim.org/entry/120436.
- “Lynch Syndrome.” National Cancer Institute, U.S. Department of Health and Human Services, 4 June 2015, https://www.cancer.gov/types/colorectal/hp/lynch-pdq.
- “MSH2.” Seattle Children’s Hospital – Center for Mendelian Genomics, University of Washington, 29 Aug. 2020, http://www.seattlechildrens.org/research/center-for-mendelian-genomics/genes-and-diseases/genes/msh2/.
- “MSH2.” Cancer Genetics, Chapelle, Paris, France, 29 July 2020, https://www.humpath.com/IMG/html/MSH2.html.