A Pathogenic Variant Reclassified to the Pseudogene PMS2P1 in a Patient with Suspected Hereditary Cancer - Case Report

Sep 24, 2026

The PMS2 gene participates in DNA mismatch repair, and its deficiencies are linked to Lynch Syndrome (LS), which confers increased risk for colorectal, endometrial, ovarian, breast, and other cancers. Germline pathogenic PMS2 variants account for up to 5% of LS cases, but prevalence estimates can be distorted by homologous pseudogenes. This case describes a 44-year-old woman with early breast cancer and no significant family history, where a variant was mapped to the PMS2P1 pseudogene, leading to reclassification as not hereditary cancer-related.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages8

Reading Time20 min

AccessFree to download

Abstract

Introduction

Lynch syndrome and mismatch repair genes

PMS2 structure and pseudogene complexity

Case Presentation

Case Report A Pathogenic Variant Reclassiﬁed to the Pseudogene PMS2P1 ina Patient with Suspected Hereditary Cancer Veronica Fragoso-Ontiveros 1, Marcela Angelica De la Fuente-Hernandez 1, Vincent Gonzalez-Osnaya 1, Mario Gamez-Rosales 2, Maria Delia Perez-Montiel 2, David Isla-Ortiz 3, David Francisco Cantu-De Leon 4 and Rosa Maria Alvarez-Gomez 1, * Citation: Fragoso-Ontiveros, V.; De la Fuente-Hernandez, M.A.; Gonzalez-Osnaya, V.; Gamez-Rosales, M.; Perez-Montiel, M.D.; Isla-Ortiz, D.; Cantu-De Leon, D.F.; Alvarez-Gomez, R.M. A Pathogenic Variant Reclassiﬁed to the Pseudogene PMS2P1 in a Patient with Suspected Hereditary Cancer. Int. J. Mol. Sci. 2023, 24, 1398 . [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms24021398 Academic Editor: Paola Ghiorzo Received: 21 December 2022 Revised: 4 January 2023 Accepted: 8 January 2023 Published: 11 January 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Hereditary Cancer Clinic, National Cancer Institute, San Fernando 22, Secciân XVI, Tlalpan, Mexico City 14070, Mexico 2 Pathology Direction, National Cancer Institute, Mexico City 14080, Mexico 3 Gineco-Oncology Department, National Cancer Institute, Mexico City 14080, Mexico 4 Research Direction, National Cancer Institute, Mexico City 14080, Mexico * Correspondence: [ralvarezg@incan.edu.mx](ralvarezg@incan.edu.mx) Abstract: The PMS2 gene is involved in DNA repair by the mismatch repair pathway. Deﬁciencies in this mechanism have been associated with Lynch Syndrome (LS), which is characterized by a high risk for colorectal, endometrial, ovarian, breast, and other cancers. Germinal pathogenic variants of PMS2 are associated with up to 5% of all cases of LS. The prevalence is overestimated for the existence of multiple homologous pseudogenes. We report the case of a 44-year-old woman diagnosed with breast cancer at 34 years without a relevant cancer family history. The presence of pathogenic variant NM_ 000535.7:c.1A > T,(p.Met1Leu) in PMS2 was determined by next-generation sequencing analysis with a panel of 322 cancer-associated genes and conﬁrmed by capillary sequencing in the patient. The variant was determined in six family members (brothers, sisters, and a son) and seven non-cancerous unrelated individuals. Analysis of the ampliﬁed region showed high homology of PMS2 with ﬁve of its pseudogenes. We determined that the variant is associated with the PMS2P1 pseudogene following sequence alignment analysis. We propose considering the variant c.1A > T,(p.Met1Leu) in PMS2 for reclassiﬁcation as not hereditary cancer-related, given the impact on the diagnosis and treatment of cancer patients and families carrying this variant. Keywords: PMS2; pseudogene; pathogenic variant; Lynch Syndrome; reclassiﬁcation; hereditary cancer 1. Introduction Lynch syndrome (LS), or Hereditary Non-Polyposis Colorectal Cancer (HNPCC), is an autosomal dominant inherited cancer syndrome. LS is associated with an increased risk of colorectal, endometrial, ovarian, and breast cancer [1–4] . Germinal pathogenic variants in the DNA mismatch repair (MMR) pathway are involved in LS. The central genes in LS are MLH1, MSH2, MSH6, PMS2, and EPCAM [5,6] . Since the genetic predisposition for LS is related to pathogenic variants in one of the four MMR genes, most LS cancers show an MMRdeﬁciency, microsatellite instability, and activation of the immune response system. Hence, LS cancer patients may be optimal candidates for immune checkpoint-based therapies [7] . ThePMS2 (PMS1 Homolog 2) gene is located on chromosome 7 with an approximate length of 38,000 base pairs contained in 15 exons.

FAQs

What role does PMS2 play in Lynch syndrome risk?

PMS2 is involved in DNA repair via the mismatch repair pathway. Deficiencies in this mechanism are associated with Lynch Syndrome, which increases cancer risk across multiple organs.

How was the PMS2 variant characterized in the patient?

The variant was identified using next-generation sequencing with a 322-gene cancer panel and then confirmed by capillary sequencing.

Why was the PMS2 variant reclassified in this case?

High sequence homology between PMS2 and multiple pseudogenes complicated interpretation. Sequence alignment showed the variant aligned with the PMS2P1 pseudogene, so it was proposed as not hereditary cancer-related.

Sep 24, 2026

Uploaded by RuangKosong