PMS2 was first reported in relation to AD Lynch Syndrome in 1994 (Nicolaides et al., PMID: 8072530). Lynch syndrome is a cancer-predisposing syndrome characterized by predisposition to a wide variety of cancers, including neoplasms of the digestive tract, urinary tract, kidney, endometrium, ovary, brain, and prostate, as well as sebaceous skin tumors, depending on the gene involved. Tumors may occur at any age but often arise at earlier ages in adults than the corresponding tumors in the general population (Orphanet). More recent studies suggest that PMS2 causes a small increased risk of colon and endometrial cancer compared with other Lynch syndrome genes and the risk of other Lynch syndrome tumors was unclear (PMID: 30161022). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in inheritance pattern and phenotypic variability for two different PMS2 disorders. Therefore, the following disease entities have been split into multiple disease entities, autosomal recessive constitutional mismatch repair deficiency (CMMRD) (OMIM:619101, MONDO:0010159). The split curation for AR CMMRD has been curated separately from this curation for Lynch syndrome. Fifteen variants (e.g. missense, in-frame indel, frameshift, large deletion) that have been reported in 16 probands in 9 publications (PMIDs: 8072530, 16619239, 23012243, 31992580, 23709753, 27435373, 15887124, 15872200, 31860975) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is known to be LOF. This gene-disease association is also supported by experimental evidence (e.g. animal models, expression studies, in vitro functional assays; 5.5 points) (PMIDs: 10753224, 34489406, 20624957, 27435373, 24027009). Heterologous PMS2 knock-out mice are susceptible to intestinal tumors located mainly in the small intestine when treated with exogenous carcinogen (PMID: 10753224). Mouse models with Pms2 knock-in of c.1993A>G, which is equivalent to human c.2002A>G, results in an attenuated form of both CMMRD in homozygous state and Lynch Syndrome in heterozygotes (PMID: 34489406). In summary, PMS2 is definitively associated with AD Lynch 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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