\PMS2 was first reported in relation to autosomal recessive constitutional mismatch repair deficiency (CMMRD) syndrome in 2000 (De Rosa et al. PMID: 10763829). Other mismatch repair (MMR) genes MLH1, MSH2 and MSH6 also cause CMMRD syndrome. CMMRD syndrome is a rare disease that greatly increases the risk of developing childhood cancer(s) such as colorectal cancers, glioblastoma, leukemia or lymphoma. Other phenotypes of CMMRD include café-au-lait spots or hypopigmentation. Note that PMS2 related cMMRD is also associated with a significant B cell-intrinsic class switch recombination defect. Three patients with MMR phenotypes have been reported with variable hypogammaglobulinemia, two of whom also have hyper-IgM syndrome (PMID: 18824584). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in the inheritance pattern and phenotypic variability in terms of cancer spectrum and age of onset between CMMRD and Lynch syndrome. Therefore, this curation focuses on CMMRD and Lynch syndrome is curated separately. 9 variants (2 missense, 2 nonsense, and 5 frameshift) have been reported in 6 probands with biallelic variants in 5 publications (PMIDs: 10763829, 15077197, 14574005, 17557300, 18030674) are included in this curation. IHC and western blot show absence of PMS2 protein in non-malignant patient tissues. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by animal models and in vitro functional assays (6.5 points. PMIDs: 9500552, 9927034, 11809679, 15340263, 16204034, 17557300, 18030674). Multiple PMS2 deficient mouse models have been established to show consistent phenotypes with cMMRD patients by developing lymphoma, leiomyosarcoma and myxoid liposarcoma. In summary, there is definitive evidence to support the relationship between PMS2 and autosomal recessive CMMRD syndrome . This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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