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Characterisation of heterozygous PMS2 variants in French patients with Lynch syndrome
  1. Qing Wang1,
  2. Julie Leclerc2,
  3. Gaëlle Bougeard3,
  4. Sylviane Olschwang4,
  5. Stéphanie Vasseur3,
  6. Kévin Cassinari3,
  7. Denis Boidin5,
  8. Cédrick Lefol1,
  9. Pierre Naïbo1,
  10. Thierry Frébourg3,
  11. Marie Pierre Buisine2,
  12. Stéphanie Baert-Desurmont3
  13. French Consortium of Oncogenetic laboratories for colorectal cancers, Unicancer Cancer Genetic Group (GGC)
  1. 1 Centre Léon Bérard, Laboratory of constitutional genetics for frequent cancers HCL-CLB, Lyon, France
  2. 2 Inserm UMR-S 1172, JPA Research Center, Lille University, and Department of Biochemistry and Molecular Biology, Lille University Hospital, Lille, France
  3. 3 Department of Genetics, Rouen University Hospital and UNIROUEN, Normandy Centre for Genomic and Personalized Medicine, Rouen, France
  4. 4 Aix Marseille Université, INSERM GMGF UMR 1251; Département de Génétique Médicale, Hôpital Européen & Groupe Ramsay Générale de Santé, Hôpital Clairval, Aix Marseille Université, Marseille, France
  5. 5 Department of Biochemistry and Molecular Biology, Lille University Hospital, Lille, France
  1. Correspondence to Dr Qing Wang, Laboratory of constitutional genetics for frequent cancers HCL-CLB, Centre Leon Berard, Lyon 69008, France;{at}


Background Heterozygous germline PMS2 variants are responsible for about 5% of Lynch syndrome (LS) but their prevalence is most likely underestimated because of complicated routine screening caused by highly homologous pseudogenes. Consequently, there is limited knowledge on the implication of the PMS2 gene in LS.

Methods We report 200 PMS2 heterozygous variants identified in 195 French patients, including 112 unique variants classified as class-3/4/5.

Results Genomic rearrangements account for 18% of alterations. The c.137G>T variant was observed in 18% of the patients, but a founder effect could not be clearly identified by haplotype analysis. 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. Seven patients developed colorectal cancers before the age of 30 with the youngest at the age of 21. Only 6.2% of class-4/5 carriers had a family history fulfilling Amsterdam I/II criteria among patients with available data. Tumours from PMS2 variant carriers exhibited microsatellite instability (96%) and loss of PMS2 expression (76%), confirming the high predictive value of somatic analysis.

Conclusion Our results provide further insight into the role of the PMS2 gene in LS. While PMS2 variants are mostly detected in families not fulfilling Amsterdam criteria, which supports their lower penetrance, they can nevertheless cause early-onset cancers, highlighting the variability of their penetrance.

  • cancer predisposition
  • Lynch syndrome
  • germline variant
  • MMR deficiency
  • PMS2

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  • Contributors SV, KC, DB and CL conducted variant identification in the three laboratories participating to the study. DB was involved in haplotype analysis. QW, JL, GB, SO, PN, MPB, TF and SBD as well as the French consortium were involved in biological and clinical data collection and variant interpretation. QW, JL, GA, MPB and SBD edited the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available in a public, open access repository.