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

Melyssa Aronson, Chrystelle Colas, Andrew Shuen, Heather Hampel, William D. Foulkes, Hagit Baris Feldman, Yael Goldberg, Martine Muleris, Kami Wolfe Schneider, Rose B. McGee, Kory Jasperson, Arun Rangaswami, Laurence Brugieres, Uri Tabori

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)318-327
Number of pages10
JournalJournal of Medical Genetics
Issue number4
StatePublished - 1 Apr 2022


  • Diagnosis
  • Gastrointestinal diseases
  • Genetics
  • Heredity
  • Medical
  • Medical oncology


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