Assessment of the 2022 Constitutional Mismatch Repair Deficiency Syndrome Diagnostic Criteria Using the International Replication Repair Deficiency Consortium

Purpose Constitutional mismatch repair deficiency syndrome (CMMRD) syndrome, caused by inherited biallelic mismatch repair (MMR) gene loss, is characterized by early-onset cancers and neurofibromatosis Type 1 (NF1) features. Genetic heterogeneity of syndromes with replication repair deficiency (RRD) and non-RRD conditions (eg, Lynch syndrome (LS) and NF1, respectively) leads to diagnostic challenges. Seven diagnostic criteria (CMMRD1-CMMRD7) were established in 2022 incorporating germline results, ancillary tests, and clinical manifestation. This study reviews the use of these criteria in identifying CMMRD. Methods Individuals suspected of CMMRD referred to the International Replication Repair Deficiency Consortium in Toronto, Canada, had clinical manifestation, family history, germline, MMR immunohistochemistry (IHC) of non-neoplastic (NN-IHC) and tumor tissue, and LOGIC obtained to assess the diagnostic criteria. Results A total of 580 individuals were identified, with 159 excluded because of insufficient information resulting in 421 individuals assessed using the diagnostic criteria. Of these, 358 (85%) were classified as CMMRD/suspected CMMRD (n = 270), LS/likely LS (n = 78), or other hereditary conditions (n = 10). Sixty-three individuals could not be classified because of the lack of or discordant results. Of the 270 patients with CMMRD syndrome, 241 met the published criteria and 29 were suspected of CMMRD on the basis of fulfilling criteria with a discordant functional result or suspicious genotype/phenotype. CMMRD1-CMMRD7 criteria were all identified, with 57% (n = 137) fulfilling CMMRD1 criteria. Early-onset gliomas and GI cancers occurred in LS, POLE , TP53 , and NF1. Digenic LS and concurrent hereditary cancer syndromes were identified. Conclusion The 2022 CMMRD syndrome diagnostic criteria provided a useful framework for establishing CMMRD syndrome and distinguishing it from similar conditions. A clinically meaningful subset remained difficult to classify despite suspicion of CMMRD. Refinement of CMMRD syndrome diagnostic criteria may address atypical presentation and discordant functional results. Limitations include incomplete availability of germline/functional testing, discordant/inconclusive results, and inherent referral bias to a specialized RRD consortium.