Pms2 is one of the four susceptibility genes in Lynch syndrome (LS), a key DNA mismatch repair (MMR) gene [5]. The MMR pathway is crucial for maintaining genomic integrity, and Pms2 functions within this pathway to rectify DNA replication errors [4].

Heterozygous germline Pms2 variants are responsible for about 5% of LS, but the prevalence may be underestimated due to pseudogenes [1]. Among class-4/5 variant carriers, the median age at first tumour onset was 49 years, with a predominance of colorectal (80%) and endometrial (8.1%) cancers. Some patients developed colorectal cancers before 30 years old [1]. Pms2 mutations contribute significantly to LS, yet the penetrance for monoallelic mutation carriers seems lower than for other MMR genes [2]. In a large cohort, 52 different pathogenic Pms2 variants were found, explaining many LS and a few constitutional mismatch repair deficiency (CMMRD) patients. Most Pms2 mutation carriers showed isolated loss of Pms2 in their tumors [3]. Pms2 knockdown cells with reduced expression levels had significantly decreased MMR efficiency [5]. A Pms2 germline heterozygous mutation (c.943C>T) was found in a family with LS-associated cancers like colon, gastric, and ovarian cancer [6].

In conclusion, Pms2 is essential for DNA mismatch repair, and its mutations are associated with LS and other cancers. Studies on Pms2, including those related to its germline mutations, help in understanding the mechanisms of LS and potentially contribute to improved counseling and cancer surveillance strategies for affected individuals.

References:

1. Wang, Qing, Leclerc, Julie, Bougeard, Gaëlle, Buisine, Marie Pierre, Baert-Desurmont, Stéphanie. 2020. Characterisation of heterozygous PMS2 variants in French patients with Lynch syndrome. In Journal of medical genetics, 57, 487-499. doi:10.1136/jmedgenet-2019-106256. https://pubmed.ncbi.nlm.nih.gov/31992580/

2. Senter, Leigha, Clendenning, Mark, Sotamaa, Kaisa, Jenkins, Mark A, de la Chapelle, Albert. 2008. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. In Gastroenterology, 135, 419-28. doi:10.1053/j.gastro.2008.04.026. https://pubmed.ncbi.nlm.nih.gov/18602922/

3. van der Klift, Heleen M, Mensenkamp, Arjen R, Drost, Mark, Wijnen, Juul T, Tops, Carli M J. 2016. Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency Syndrome. In Human mutation, 37, 1162-1179. doi:10.1002/humu.23052. https://pubmed.ncbi.nlm.nih.gov/27435373/

4. Blount, J, Prakash, A. 2018. The changing landscape of Lynch syndrome due to PMS2 mutations. In Clinical genetics, 94, 61-69. doi:10.1111/cge.13205. https://pubmed.ncbi.nlm.nih.gov/29286535/

5. Kasela, Mariann, Nyström, Minna, Kansikas, Minttu. 2019. PMS2 expression decrease causes severe problems in mismatch repair. In Human mutation, 40, 904-907. doi:10.1002/humu.23756. https://pubmed.ncbi.nlm.nih.gov/30946512/

6. Guo, Xiaoqing, Wu, Weimin, Gao, Hao, Zhu, Yong, Liu, Na. 2019. PMS2 germline mutation c.943C>T (p.Arg315*)-induced Lynch syndrome-associated ovarian cancer. In Molecular genetics & genomic medicine, 7, e721. doi:10.1002/mgg3.721. https://pubmed.ncbi.nlm.nih.gov/31056861/