Diagnostic criteria for constitutional mismatch repair deficiency (CMMRD): recommendations from the international consensus working group

J Med Genet. 2022 Apr;59(4):318-327. doi: 10.1136/jmedgenet-2020-107627. Epub 2021 Feb 23.


Background: Constitutional mismatch repair deficiency syndrome (CMMRD) is the most aggressive cancer predisposition syndrome associated with multiorgan cancers, often presenting in childhood. There is variability in age and presentation of cancers and benign manifestations mimicking neurofibromatosis type 1. Genetic testing may not be informative and is complicated by pseudogenes associated with the most commonly associated gene, PMS2. To date, no diagnostic criteria exist. Since surveillance and immune-based therapies are available, establishing a CMMRD diagnosis is key to improve survival.

Methods: In order to establish a robust diagnostic path, a multidisciplinary international working group, with representation from the two largest consortia (International Replication Repair Deficiency (IRRD) consortium and European Consortium Care for CMMRD (C4CMMRD)), was formed to establish diagnostic criteria based on expertise, literature review and consensus.

Results: The working group established seven diagnostic criteria for the diagnosis of CMMRD, including four definitive criteria (strong evidence) and three likely diagnostic criteria (moderate evidence). All criteria warrant CMMRD surveillance. The criteria incorporate germline mismatch repair results, ancillary tests and clinical manifestation to determine a diagnosis. Hallmark cancers for CMMRD were defined by the working group after extensive literature review and consultation with the IRRD and C4CMMRD consortia.

Conclusions: This position paper summarises the evidence and rationale to provide specific guidelines for CMMRD diagnosis, which necessitates appropriate surveillance and treatment.

Keywords: diagnosis; gastrointestinal diseases; genetics; heredity; medical; medical oncology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain Neoplasms* / diagnosis
  • Brain Neoplasms* / genetics
  • Brain Neoplasms* / therapy
  • Colorectal Neoplasms* / diagnosis
  • Colorectal Neoplasms* / epidemiology
  • Colorectal Neoplasms* / genetics
  • Consensus
  • DNA Mismatch Repair / genetics
  • Humans
  • Mismatch Repair Endonuclease PMS2 / genetics
  • Neoplastic Syndromes, Hereditary* / diagnosis
  • Neoplastic Syndromes, Hereditary* / genetics
  • Neoplastic Syndromes, Hereditary* / therapy


  • Mismatch Repair Endonuclease PMS2

Supplementary concepts

  • Turcot syndrome