Deciphering the Pathogenicity of the PMS2 p.His701Gln Variant in a Family with Elderly-Onset Extracolonic Lynch Syndrome
5 affiliations
- 1Medical Genetics, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy
- 2Department of Molecular Medicine, University of Rome La Sapienza, 00161 Rome, Italy
- 3Histopathology Unit, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy
- 4Medical Direction, National Institute of Gastroenterology, IRCCS “Saverio de Bellis”, Research Hospital, 70013 Bari, Italy
- 5Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari Aldo Moro, 70124 Bari, Italy
Abstract
Missense variants in PMS2 remain difficult to interpret in Lynch Syndrome (LS), particularly when clinical evidence is limited. We investigated the PMS2, NM_000535.7: c.2103T>A; p.His701Gln (p.H701Q) variant, currently classified as a variant of uncertain significance (VUS), identified in a 71-year-old patient with small intestinal adenocarcinoma. To clarify its clinical significance, we combined clinical, in silico, and functional analyses. Computational predictions consistently pointed to a deleterious effect, with AlphaMissense assigning a highly damaging score and most independent predictors supporting the same interpretation. H701Q affects the highly conserved C-terminal region of PMS2, close to the functionally critical Glu705 residue. In HEK-293T cells, PMS2-H701Q showed markedly reduced protein levels compared with wild-type PMS2, supporting an effect on protein stability. Co-immunoprecipitation experiments further showed a substantial reduction in the interaction between PMS2-H701Q and MLH1, indicating impaired MutLα complex formation. Both effects were comparable to those observed for the pathogenic PMS2-E705K control. Overall, the agreement between computational and functional findings provides compelling evidence for a deleterious effect of H701Q and strengthens its clinical interpretation. Collectively, these findings demonstrate the utility of functional evidence under the ClinGen-InSiGHT PMS2-specific ACMG/AMP variant classification guidelines and support reclassifying the PMS2, NM_000535.7: c.2103T>A; p.His701Gln (p.H701Q) variant from a Variant of Uncertain Significance (VUS) to likely pathogenic.
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BibTeX
@article{candela2026deciphering,
title = {{Deciphering the Pathogenicity of the PMS2 p.His701Gln Variant in a Family with Elderly-Onset Extracolonic Lynch Syndrome}},
author = {Erica Candela and Giovanna Forte and Matteo Iacoviello and Antonia Lucia Buonadonna and Anna Maria Valentini and Martina Lepore Signorile and Paola Sanese and Katia De Marco and Andrea Manghisi and Nicoletta Maria Tutino and Emanuele Tatò and Candida Fasano and Vittoria Disciglio and Valentina Grossi and Cristiano Simone},
journal = {Cells},
year = {2026},
month = oct,
doi = {10.3390/cells15211990},
url = {https://www.mdpi.com/2073-4409/15/21/1990},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Deciphering the Pathogenicity of the PMS2 p.His701Gln Variant in a Family with Elderly-Onset Extracolonic Lynch Syndrome
AU - Erica Candela
AU - Giovanna Forte
AU - Matteo Iacoviello
AU - Antonia Lucia Buonadonna
AU - Anna Maria Valentini
AU - Martina Lepore Signorile
AU - Paola Sanese
AU - Katia De Marco
AU - Andrea Manghisi
AU - Nicoletta Maria Tutino
AU - Emanuele Tatò
AU - Candida Fasano
AU - Vittoria Disciglio
AU - Valentina Grossi
AU - Cristiano Simone
PY - 2026
DA - 2026/10/31
JO - Cells
DO - 10.3390/cells15211990
UR - https://www.mdpi.com/2073-4409/15/21/1990
AB - Missense variants in PMS2 remain difficult to interpret in Lynch Syndrome (LS), particularly when clinical evidence is limited. We investigated the PMS2, NM_000535.7: c.2103T>A; p.His701Gln (p.H701Q) variant, currently classified as a variant of uncertain significance (VUS), identified in a 71-year-old patient with small intestinal adenocarcinoma. To clarify its clinical significance, we combined clinical, in silico, and functional analyses. Computational predictions consistently pointed to a deleterious effect, with AlphaMissense assigning a highly damaging score and most independent predictors supporting the same interpretation. H701Q affects the highly conserved C-terminal region of PMS2, close to the functionally critical Glu705 residue. In HEK-293T cells, PMS2-H701Q showed markedly reduced protein levels compared with wild-type PMS2, supporting an effect on protein stability. Co-immunoprecipitation experiments further showed a substantial reduction in the interaction between PMS2-H701Q and MLH1, indicating impaired MutLα complex formation. Both effects were comparable to those observed for the pathogenic PMS2-E705K control. Overall, the agreement between computational and functional findings provides compelling evidence for a deleterious effect of H701Q and strengthens its clinical interpretation. Collectively, these findings demonstrate the utility of functional evidence under the ClinGen-InSiGHT PMS2-specific ACMG/AMP variant classification guidelines and support reclassifying the PMS2, NM_000535.7: c.2103T>A; p.His701Gln (p.H701Q) variant from a Variant of Uncertain Significance (VUS) to likely pathogenic.
SN - 2073-4409
ER -