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

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

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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.

Epidemiology/Prevalence

Estimated birth incidence of 1 per million

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

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.
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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Notes

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Prior Author(s):