PMS2

Inheritance Pattern: AR

Disease ID:MONDO:0010159

Submitter: ClinGen

\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.

Inheritance Pattern: AR

Disease ID:MONDO:0010159

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0030843

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0013699

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0013699

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0008018

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0016419

Submitter: ClinGen

PMS2 encodes a protein playing a key role in the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. PMS2 forms heterodimers with MLH1 to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is necessary for removal of the mismatched DNA. Defective MMR pathway is responsible for microsatellite instability, a type of genomic instability that is characteristic for tumor cells. *PMS2* has been linked to Lynch Syndrome (autosomal dominant) and mismatch repair cancer syndrome (autosomal recessive), which were curated separately. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, curations to refute or dispute can be split when needed. This curation focuses on disputing the association with breast cancer. Evidence curated in this gene-disease relationship includes case-control and experimental data. **Summary of Case-Control Data: 0 point** This gene-disease relationship has been studied in at least 3 case-control studies at the aggregate variant level. In 2021, a large case-control study [BCAC (PMID: 33471991) with more than 48 thousand cases and controls] did not identify a significant association of aggregate loss of function (LOF) variants in *PMS2* and breast cancer. Likewise, another two large case-control studies published in 2017 screened breast cancer cases from commercial laboratories and did not find significant association of pathogenic mutations in *PMS2* with breast cancer (PMID: 28418444, 35172496). **Summary of Experimental Data: 0 point** Baker et al. (PMID: 7628019) demonstrated that mice with homozygous knockout of *PMS2* did not develop tumors in breast or ovarian tissues. However, considering the short lifespan of mice, this evidence is not conclusive. Therefore, this evidence did not be scored or listed as a contradiction. **Overall Summary:** In summary, large breast cancer case-control studies have shown the lack of significant association of *PMS2* and breast cancer. However, considering that correct variant analysis of *PMS2* is complex due to the presence of multiple pseudogenes and the occurrence of gene conversion, more evidence is needed to either support or entirely refute the role of *PMS2* in hereditary breast cancer. The relationship between *PMS2* and autosomal dominant hereditary breast cancer has currently been disputed. This gene-disease pair was originally evaluated as disputed by the Breast/Ovarian Cancer GCEP on 11/8//2017. This re-curation was approved by the ClinGen Hereditary Diseases GCEP on 6/9/2023 (SOP Version 9).

Inheritance Pattern: AD

Disease ID:MONDO:0005835

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0008315

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0005835

Submitter: ClinGen

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.

Inheritance Pattern: AD

Disease ID:MONDO:0007254

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0030843

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0005212

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0013699

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0008170

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0009831

Submitter: Genomics England PanelApp