A PMS2 non-canonical splicing site variant leads to aberrant splicing in a patient suspected for lynch syndrome.

Abstract

The PMS2 gene is one of the DNA mismatch repair genes (MMR) implicated in Lynch syndrome (LS). A subset of PMS2 pathogenic variants (PVs) are splice variants mostly affecting canonical GT/AG splicing sequences. However, the majority of the intronic variants outside canonical splice sites remained as variants of unknown significance, even though some of them would alter the splicing process. In this report, we describe the analysis of such an intronic variant (c.251-5T > C) detected in an 82-year-old patient diagnosed with endometrial cancer displaying microsatellite instability and the loss of PMS2 expression displayed. RNA analysis demonstrated that this variant lead to the complete exon 4 skipping, resulting in the synthesis of a truncated protein. This finding shows the relevance of functional RNA analysis in the non-canonical intronic variant assessment and the importance of systematic evaluation of MSI/loss of expression of MMR genes for LS screening in patients with endometrial cancers.

• Authors: Ahmed Bouras, Pierre Naibo, Clémentine Legrand, François Le Marc'hadour, Eric Ruano, Chloé Grand-Masson, Cedrick Lefol, Qing Wang
• Journal: Familial cancer (Fam Cancer) Vol. 22 Issue 3 Pg. 303-306 (Jul 2023) ISSN: 1573-7292 [Electronic] Netherlands
• PMID: 36445599 (Publication Type: Case Reports, Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature B.V.

Chemical References

• Mismatch Repair Endonuclease PMS2
• MutL Protein Homolog 1
• PMS2 protein, human

Topics

• Humans
• Aged, 80 and over
• Colorectal Neoplasms, Hereditary Nonpolyposis (diagnosis)
• Mismatch Repair Endonuclease PMS2 (genetics, metabolism)
• Germ-Line Mutation
• Mutation
• DNA Mismatch Repair (genetics)
• Microsatellite Instability
• MutL Protein Homolog 1 (genetics)