| domain | key quantitative findings | principal recent source (author/year/journal/DOI or PMID) | ontology suggestions |
|---|---|---|---|
| Genetics / etiology | CMMRD is caused by biallelic germline pathogenic variants in mismatch repair genes **MLH1, MSH2, MSH6, PMS2**; median diagnosis age **8.9 years** in a 201-patient cohort; **PMS2 >60%** of cases, **MSH6 20-30%**, **MLH1/MSH2 10-20%**; consanguinity reported in **39-45%** of families; birth prevalence estimated at approximately **1 in 1,000,000** (pqac-00000001, pqac-00000003, pqac-00000000) | Ercan et al., 2024, *Lancet Oncology*, DOI: 10.1016/S1470-2045(24)00026-3; Vasen et al., 2026, *Familial Cancer*, DOI: 10.1007/s10689-026-00584-x | Gene: **MLH1, MSH2, MSH6, PMS2**; GO: **DNA mismatch repair**; MONDO: constitutional mismatch repair deficiency; HP: **Autosomal recessive inheritance** |
| Major phenotype / natural history | In the IRRDC cohort (**n=201**), **97%** developed cancer with **339 cancers** total and **90% cumulative incidence by age 18**; spectrum: **CNS 51%**, **gastrointestinal 22%**, **hematological 18%**, **other 9%**; median interval between multiple cancers **1.9 years**; dermatologic manifestations in **93%**; CNS tumors had the poorest outcome with **39% 10-year survival** vs **67%** hematologic and **89%** GI cancers (pqac-00000001, pqac-00000012) | Ercan et al., 2024, *Lancet Oncology*, PMID: **38552658**, DOI: 10.1016/S1470-2045(24)00026-3 | HP: **Cafe-au-lait macules**, **Brain neoplasm**, **Colorectal carcinoma**, **Lymphoma**, **Multiple primary neoplasms**; UBERON: **brain**, **colon**, **small intestine**, **hematopoietic system** |
| Diagnosis | Germline testing for biallelic pathogenic/likely pathogenic MMR variants is the diagnostic gold standard; non-neoplastic tissue IHC showing complete MMR protein loss has reported **>90% sensitivity** and approximately **100% specificity**; LOGIC assay was **100% sensitive and specific** in childhood cancers (**N=376**) and outperformed MSI panel (**14% sensitivity**), IHC (**86%**), and TMB (**80%**); blood/saliva DNA distinguished CMMRD from other syndromes (**n=277**) (pqac-00000009, pqac-00000013) | Chung et al., 2023, *Journal of Clinical Oncology*, DOI: 10.1200/JCO.21.02873; summarized in Vasen et al., 2026, *Familial Cancer*, DOI: 10.1007/s10689-026-00584-x | GO: **microsatellite instability**, **DNA mismatch repair**; HP: **Abnormality of DNA repair**; NCIT: **Immunohistochemistry**, **Whole exome sequencing**, **Whole genome sequencing** |
| Surveillance | Consensus surveillance includes **CBC every 6 months from age 1**, optional **abdominal ultrasound every 6 months from age 1**, **brain MRI every 6-12 months from age 2** (or from diagnosis/first year in some protocols), **ileocolonoscopy annually from age 6-8**, **upper endoscopy/videocapsule annually from age 8-10**, **whole-body MRI annually from age 6** or at diagnosis, and **annual gynecologic/urologic screening from age 20**; surveillance participation was associated with **79% 4-year survival** versus **15%** in non-participants, and digestive surveillance achieved **100% 5-year survival** in reported experience (pqac-00000008, pqac-00000009, pqac-00000011, pqac-00000013) | C4CMMRD/IRRDC guidance summarized in Shuen, 2025; Vasen et al., 2026, *Familial Cancer*, DOI: 10.1007/s10689-026-00584-x | NCIT: **Magnetic Resonance Imaging**, **Colonoscopy**, **Upper Gastrointestinal Endoscopy**, **Complete Blood Count**; UBERON: **brain**, **colon**, **stomach**, **small intestine**, **whole body** |
| Treatment | Immune checkpoint blockade is the major recent advance. In pediatric hypermutant/MMRD cancers treated with nivolumab (**NCT02992964**), best overall response was **50%** and **2-year OS 50%**; **4** children, including **3** with refractory malignant gliomas, achieved complete remission at median follow-up **37 months**; in registry data, objective responses were **64%** for CNS tumors and **100%** for non-CNS solid tumors with nivolumab or pembrolizumab. Temozolomide resistance is a recurring concern in MMR-deficient gliomas (pqac-00000015, pqac-00000016, pqac-00000010) | Das et al., 2023, *Clinical Cancer Research*, DOI: 10.1158/1078-0432.CCR-23-0411; Vasen et al., 2026, *Familial Cancer*, DOI: 10.1007/s10689-026-00584-x | NCIT: **Nivolumab**, **Pembrolizumab**, **Immune Checkpoint Inhibitor Therapy**; GO: **adaptive immune response**, **T cell mediated cytotoxicity** |
| Evidence gaps / limitations | Important gaps remain in standardized confirmation of hypomorphic variants and genotype-phenotype mismatches; PMS2 testing is complicated by pseudogene interference and a high VUS burden (**49%** cited in summary evidence); some older 'likely CMMRD' categories are being abandoned in favor of conclusive molecular/functional evidence; surveillance and treatment evidence remains largely observational and registry-based, with limited prospective pediatric trial data (pqac-00000003, pqac-00000013, pqac-00000014) | Gallon et al., 2024, *NPJ Precision Oncology*, DOI: 10.1038/s41698-024-00603-z; Vasen et al., 2026, *Familial Cancer*, DOI: 10.1007/s10689-026-00584-x | NCIT: **Variant of Uncertain Significance**; GO: **DNA repair**; HP: **Variable expressivity** |


*Table: This table summarizes the most actionable evidence already gathered for constitutional mismatch repair deficiency across genetics, phenotype, diagnosis, surveillance, treatment, and current evidence limitations. It is useful as a compact scaffold for a disease knowledge base entry and ontology mapping.*