GTS5:Constitutional mismatch repair deficiency (CMMRD) syndrome (MLH1, PMS2, MSH2, MSH6)
 | This page is under construction |
(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)
Primary Author(s)*
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WHO Classification of Disease
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| Structure | Disease |
|---|---|
| Book | |
| Category | |
| Family | |
| Type | |
| Subtype(s) |
Related Terminology
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| Acceptable | |
| Not Recommended |
Definition/Description of Disease
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Epidemiology/Prevalence
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Genetic Abnormalities: Germline
Put your text here and fill in the table (Instructions: Describe germline alteration(s) that cause the syndrome. In the notes, include additional details about most common mutations including founder mutations, mechanisms of molecular pathogenesis, alteration-specific prognosis and any other important genetics-related information. If multiple causes of the syndrome, include relative prevalence of genetic contributions to that syndrome. Please include references throughout the table. Do not delete the table.)
| Gene | Genetic Variant or Variant Type | Molecular Pathogenesis | Inheritance, Penetrance, Expressivity | Notes |
|---|---|---|---|---|
| EXAMPLE: BRCA1 | EXAMPLE: Many | EXAMPLE: Multiple variant types leading to loss of function | EXAMPLE: Autosomal recessive,
~30% penetrant for carriers |
|
| EXAMPLE: Gene X | EXAMPLE: List the specific mutation | |||
Genetic Abnormalities: Somatic
Put your text here and fill in the table (Instructions: Describe significant second hit mutations, or somatic variants that present as a germline syndrome. In the notes, include details about most common mutations, mechanisms of molecular pathogenesis, alteration-specific prognosis and any other important genetic-related information. Please include references throughout the table. Do not delete the table.)
| Gene | Genetic Variant or Variant Type | Molecular Pathogenesis | Inheritance, Penetrance, Expressivity | Notes |
|---|---|---|---|---|
| EXAMPLE: BRCA1 | EXAMPLE: Biallelic inactivation variants | EXAMPLE: Second hit mutation can occur as copy neutral LOH, inactivating mutation, deletion, promoter hypermethylation, or a structural abnormality disrupting the gene. | ||
| EXAMPLE: BRCA1 | EXAMPLE: Reversion mutation | EXAMPLE: After exposure to certain therapies (e.g. PARP inhibitors), a second mutation may restore gene function as a resistance mechanism. | ||
Genes and Main Pathways Involved
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| Gene; Genetic Alteration | Pathway | Pathophysiologic Outcome |
|---|---|---|
| EXAMPLE: BRAF and MAP2K1; Activating mutations | EXAMPLE: MAPK signaling | EXAMPLE: Increased cell growth and proliferation |
| EXAMPLE: CDKN2A; Inactivating mutations | EXAMPLE: Cell cycle regulation | EXAMPLE: Unregulated cell division |
| EXAMPLE: KMT2C and ARID1A; Inactivating mutations | EXAMPLE: Histone modification, chromatin remodeling | EXAMPLE: Abnormal gene expression program |
Genetic Diagnostic Testing Methods
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Additional Information
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Links
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References
(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted.)
Notes
*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the Associate Editor or other CCGA representative. When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.
Prior Author(s):
OLD TEMPLATE CONTENT STARTS HERE
| This page is under construction |
(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type, which is based on current knowledge within the WHO classification books and using resources such as PubMed for the latest information. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support)
Primary Author(s)*
Put your text here (EXAMPLE: Jane Smith, PhD)
WHO Classification of Disease
(Instructions: This table’s content will be autogenerated.)
| Structure | Disease |
|---|---|
| Book | |
| Category | |
| Family | |
| Type | |
| Subtype(s) |
Definition / Description of Disease
Put your text here (Instructions: Include a brief general clinical description, diagnostic criteria, and differential diagnosis if applicable. Include disease context relative to other WHO classification categories, i.e. describe any organ-specific information pertinent to the genetic aspects of the disease across all applicable WHO classification books.) Constitutional mismatch repair deficiency syndrome (CMMRD) is an autosomal recessive cancer predisposition syndrome caused by biallelic germline mutations in one of four mismatch repair genes (MLH1, PMS2, MSH2, and MSH6). Individuals with CMMRD develop ultrahypermutated malignant gliomas, CNS embryonal tumors, and a variety of other cancers during childhood and early adulthood.[1] Affected individuals often have colorectal cancer or cancer of the small intestine prior to the second decade of life.The cutaneous phenotype in affected individuals may be remarkably similar to that seen in neurofibromatosis type I, as nearly all will have café au lait macules.[2]
Synonyms / Terminology
Put your text here (Instructions: Include currently used terms and major historical ones, adding “(historical)” after the latter.)
Not recommended: mismatch repair cancer syndrome; Turcot syndrome; brain tumor polyposis syndrome type 1.
Acceptable: biallelic mismatch repair deficiency syndrome.
Epidemiology / Prevalence
Put your text here
Estimated birth incidence of 1 per million[3]
Median age at onset is younger than 10 years
Genetic Abnormalities: Germline
Put your text here and fill in the table (Instruction: Can include references in the table. Do not delete table. If multiple causes of the syndrome, include relative prevalence of genetic contributions to that syndrome. In the notes, include additional details about most common mutations including founder mutations, mechanisms of molecular pathogenesis, alteration-specific prognosis and any other important genetic-related information with key references.)
a comparison of MLH1- and MSH2-associated CMMRD with PMS2-associated CMMRD found hematologic malignancies were 1.77-fold more prevalent in the former (P 1⁄4 .04), whereas brain tumors were 1.75-fold more frequent in the latter (P 1⁄4 .01). Furthermore, MLH1- and MSH2-associated CMMRD cancers tended to occur earlier than those associ- ated with MSH6 or PMS2,17 which reflects the MMR gene– phenotype correlation seen in LS[4]
| Gene | Genetic Variant or Variant Type | Molecular Pathogenesis | Inheritance, Penetrance, Expressivity | Notes |
| EXAMPLE: MLH1 | EXAMPLE: Many | EXAMPLE: Multiple variant types leading to loss of function | Homozygous or compound heterozygous mutations | |
| PMS2 | affected in the majority of patients with CMMRD[5].
|
|||
| MSH2 | ||||
| EXAMPLE: MSH2 | EXAMPLE: List the specific mutation |
Genetic Abnormalities: Somatic
Put your text here and fill in the table (Instruction: Describe significant second hit mutations, or somatic variants that present as a germline syndrome. Can include references in the table. Do not delete table. In the notes, include details about most common mutations, mechanisms of molecular pathogenesis, alteration-specific prognosis and any other important genetic-related information with key references.)
| Gene | Genetic Variant or Variant Type | Molecular Pathogenesis | Inheritance, Penetrance, Expressivity | Notes |
| EXAMPLE: BRCA | EXAMPLE: Biallelic inactivation variants | EXAMPLE: Second hit mutation can occur as copy neutral LOH, inactivating mutation, deletion, promoter hypermethylation, or a structural abnormality disrupting the gene. | ||
| EXAMPLE: BRCA | EXAMPLE: Gain | EXAMPLE:After exposure to certain therapies (e.g. PARP inhibitors), a second mutation may restore gene function as a resistance mechanism. |
Genes and Main Pathways Involved
Put your text here and fill in the table (Instructions: Can include references in the table. Do not delete table.)
| Gene; Genetic Alteration | Pathway | Pathophysiologic Outcome |
|---|---|---|
| EXAMPLE: BRAF and MAP2K1; Activating mutations | EXAMPLE: MAPK signaling | EXAMPLE: Increased cell growth and proliferation |
| EXAMPLE: CDKN2A; Inactivating mutations | EXAMPLE: Cell cycle regulation | EXAMPLE: Unregulated cell division |
| EXAMPLE: KMT2C and ARID1A; Inactivating mutations | EXAMPLE: Histone modification, chromatin remodeling | EXAMPLE: Abnormal gene expression program |
Genetic Diagnostic Testing Methods
Put your text here
Constitutional microsatellite instability
resolve exon 12–15 variants in PMS2 from those in the closely related PMS2CL pseudogene[6]
Additional Information
Put your text here
Links
Put a link here or anywhere appropriate in this page (Instructions: Highlight the text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the page, and search the name of the internal page to which you want to link this text, or enter an external internet address by including the "http://www." portion.)
References
- ↑ [1]
- ↑ [2]
- ↑ Suerink, Manon; et al. (2018-11-10). "Constitutional mismatch repair deficiency as a differential diagnosis of neurofibromatosis type 1: consensus guidelines for testing a child without malignancy". Journal of Medical Genetics. 56 (2): 53–62. doi:10.1136/jmedgenet-2018-105664. ISSN 0022-2593.
- ↑ Dominguez-Valentin, Mev; et al. (2020-01). "Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database". Genetics in Medicine. 22 (1): 15–25. doi:10.1038/s41436-019-0596-9. Check date values in:
|date=(help) - ↑ Wimmer, Katharina; et al. (2014-04-15). "Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium 'Care for CMMRD' (C4CMMRD)". Journal of Medical Genetics. 51 (6): 355–365. doi:10.1136/jmedgenet-2014-102284. ISSN 0022-2593.
- ↑ van der Klift, Heleen M.; et al. (2010). "Quantification of sequence exchange events betweenPMS2andPMS2CLprovides a basis for improved mutation scanning of Lynch syndrome patients". Human Mutation: n/a–n/a. doi:10.1002/humu.21229. ISSN 1059-7794.
(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted.)
Notes
*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the Associate Editor or other CCGA representative. When pages have a major update by a new author, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author. Additional global feedback or concerns are also welcome.
Prior Author(s):