GTS5:Constitutional mismatch repair deficiency (CMMRD) syndrome (MLH1, PMS2, MSH2, MSH6)

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Genetic Tumour Syndromes (Who Classification, 5th ed.)

(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)*

Jennie Thurston, PhD, FACMGG

WHO Classification of Disease

Structure Disease
Book Genetic Tumour Syndromes (5th ed.)
Category DNA repair and genomic stability
Family Mismatch repair
Type Constitutional mismatch repair deficiency (CMMRD) syndrome (MLH1, PMS2, MSH2, MSH6)
Subtype(s) N/A

Related Terminology

Acceptable N/A
Not Recommended N/A

Definition/Description of Disease

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. 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.[1]

Epidemiology/Prevalence

Estimated birth incidence of 1 per million[2]

Median age at onset is younger than 10 years

Genetic Abnormalities: Germline

A comparison of MLH1- and MSH2-associated CMMRD with PMS2-associated CMMRD found hematologic malignancies were 1.77-fold more prevalent in the former, 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 associated with MSH6 or PMS2, which reflects the MMR gene–phenotype correlation seen in LS[3]

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
MLH1 Balletic inactivation variants Homozygous or compound heterozygous mutations leading to loss of function Mutated in 10 to 20% of patients
PMS2 Balletic inactivation variants Mutated in 60% of patients[4].
MSH2 Balletic inactivation variants Mutated in 10 to 20% of patients
MSH6 Balletic inactivation variants Mutated in 20 to 30% of patients

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


Gene; Genetic Alteration Pathway Pathophysiologic Outcome
MLH1, PMS2, MSH2, MSH6; Inactivating mutations Loss of mismatch repair function in all somatic cells Abnormal regulation of apoptosis and therefore a relative growth advantage that contributes to tumour formation

Genetic Diagnostic Testing Methods

IHC

Additional Information

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Links

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References

  1. ↑ Arends, MJ, Nagtegaal, ID, Frankel, WL et al. Constitutional mismatch repair deficiency (CMMRD) syndrome (MLH1, PMS2, MSH2, MSH6). In: WHO Classification of Tumours Editorial Board. Genetic Tumour Syndromes [Internet]. Lyon (France): International Agency for Research on Cancer; 2021 [cited 2025 02 2]. (WHO classification of tumours series, 5th ed.; vol. 6). Available from: https://tumourclassification.iarc.who.int/chapters/45.
  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.
  3. ↑ 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)
  4. ↑ 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.


Notes

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Prior Author(s):

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