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Diagnostic criteria for constitutional mismatch repair deficiency (CMMRD): recommendations from the international consensus working group
  1. Melyssa Aronson1,2,
  2. Chrystelle Colas3,
  3. Andrew Shuen4,5,
  4. Heather Hampel6,
  5. William D Foulkes7,
  6. Hagit Baris Feldman8,9,
  7. Yael Goldberg10,11,
  8. Martine Muleris12,
  9. Kami Wolfe Schneider13,
  10. Rose B McGee14,
  11. Kory Jasperson15,
  12. Arun Rangaswami16,
  13. Laurence Brugieres17,18,
  14. Uri Tabori19,20
  1. 1 Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
  2. 2 Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada
  3. 3 Département de génétique, Institut Curie, Université Paris Sciences Lettres, Paris, France
  4. 4 Sickkids, Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada
  5. 5 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
  6. 6 Internal Medicine, Ohio State University Wexner Medical Center, Columbus, Ohio, USA
  7. 7 Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montreal, Quebec, Canada
  8. 8 The Genetics Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
  9. 9 Tel Aviv University Sackler Faculty of Medicine, Tel Aviv, Israel
  10. 10 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
  11. 11 The Raphael Recanati Genetic Institute, Rabin Medical Center – Beilinson Hospital, Petah Tikva, Israel
  12. 12 Inserm, Centre de Recherche Saint-Antoine, CRSA, Sorbonne Université, Paris, France
  13. 13 Section of Hematology, Oncology and Bone Marrow Transplantation, Children's Hospital Colorado, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, USA
  14. 14 Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee, USA
  15. 15 Ambry Genetics, Aliso Viejo, California, USA
  16. 16 Department of Pediatrics/Division of Hematology-Oncology, University of California San Francisco, San Francisco, California, USA
  17. 17 Department of Children and Adolescents Oncology, Gustave Roussy, Villejuif, France
  18. 18 Paris-Saclay University, Saint-Aubin, France
  19. 19 Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada
  20. 20 University of Toronto Faculty of Medicine, Toronto, Ontario, Canada
  1. Correspondence to Melyssa Aronson, Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Melyssa.Aronson{at}


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.

  • diagnosis
  • heredity
  • gastrointestinal diseases
  • genetics
  • medical
  • medical oncology

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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  • Contributors All authors contributed to planning, conduct and reporting of this work.

  • Funding The International Replication Repair Deficiency (IRRD) consortium is partially supported by grants from Stand Up to Cancer (SU2C-AACR-CT07-17), Canadian Institutes of Health Research (CIHR) (#PJT-156006 and 108188-001 as part of Joint Canada-Israel Health Research Program) and Meagan’s Walk (MW-2014-10). The C4CMMRD database is supported by La Fondation Gustave Roussy, Guérir le cancer de l’Enfant au 21ème siècle. These agencies had no involvement in the study design, analysis or interpretation of data, writing or decision to submit for publication.

  • Competing interests HH reports the following financial relationships: Scientific Advisory Board at Invitae Genetics, Medical Advisory Board at Promega, Scientific Advisory Board at Genome Medical, and consultant at 23andMe. None of the relationships presents a conflict of interest in this study. KJ is a full-time employee at Ambry Genetics. This does not present a conflict of interest in this study. LB reports grants from Fondation Gustave Roussy, during the conduct of the study. UT reports grants from SU2C Catalyst, grants from Meagan’s Walk, grants from IDRC - Joint Canada-Israel Health Program and grants from Canadian Institutes of Health, during the conduct of the study.

  • Provenance and peer review Not commissioned; externally peer reviewed.