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Insights from 2057 germline genetic tests in renal cell carcinoma patients support revisiting testing criteria

European Journal of Human Genetics (2026)Cite this article

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Abstract

Renal cell carcinoma (RCC) arises sporadically or in a hereditary context, with inherited cases accounting for less than 10%, depending on the genes analyzed. Next-generation sequencing has enabled the use of multigene panels (MGP) to characterize RCC linked to hereditary syndromes. The current French guidelines of the national reference network for hereditary renal cancers (PREDIR) recommend genetic testing for patients meeting specific clinical criteria. This study evaluates the diagnostic yield and the relevance of current criteria, the utility of MGP testing, and the added value of tumor analyses. We retrospectively analyzed 2057 RCC patients who underwent germline MGP testing across three French hospital laboratories. Tumor analysis results from 140 patients were also evaluated. The overall rate of germline pathogenic/likely pathogenic variants was 3.5%, with 39% in syndromic cases and 1.2% in apparently sporadic cases. Tumor analyses identified somatic pathogenic variants in 56.3% of cases. Our data support that the likelihood of identifying a germline PV is low in patients with sporadic single clear cell RCC, and that the clinical utility of testing all patients with other sporadic subtypes appears limited. This suggests a need to revise current testing criteria in patients with sporadic single RCC, for example, by lowering the age threshold for genetic testing from 45 to 40 years in clear cell RCC, and to 50 years in other subtypes. We also suggest incorporating tumor analyses to distinguish hereditary RCC from sporadic cases driven by tumor-specific pathogenic variants.

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Fig. 1: Diagnostic yield and genes with pathogenic variants according to clinical indications for RCC genetic testing.
Fig. 2: Diagnostic yield and genes with pathogenic variants according to RCC tumor histology and unique or multiple presentation.
Fig. 3: Oncoprint of tumors analyzed to support variant classification and diagnosis in patients without pathogenic germline variants but with a strong clinical suspicion of hereditary renal cancer.
Fig. 4: Oncoprint of tumor pathogenic variants (alterations) identified in 154 interpretable tumors analyzed according to the clinical indication to the genetic test.

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Data availability

The data supporting the findings of this study are available from the corresponding author upon request.

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Acknowledgements

We sincerely thank all the prescribers of the genetic tests of the patients included in this study: Caroline Abadie, Séverine Audebert-Bellanger, Michel Bahuau, Patrick Benusiglio, Odile Bera, Pascaline Berthet, Valérie Bonadona, Marie-Noelle Bonnet-Dupeyron, Virginie Bubien, Bruno Buecher, Anne-Claire Bursztejn, Alain Calender, Frédérique Carrer-Pigeon, François Cartault, Hélène Castanie, Dominique Chauveau, Aldja Chebah, Jean Chiesa, Bérangère Coestier, Odile Cohen-Haguenauer, Chrystelle Colas, Marie-Agnès Collonge-Rame, Cindy Colson, François Cornelis, Carole Corsini, Edouard Cottereau, Isabelle Coupier, Louise Crivelli, Thomas Cuny, Veronica Cusin, Antoine Dardenne, Françoise Davis-Brucker, Florence Demurger, Philippe Denizeau, Anne-Sophie Denomme-Pichon, Pierre Devulder, Marion Dhooge, Béatrice Doray, Hélène Dreyfus, Anne Durlach, Sophie Dussart, François Eisinger, Clémence Evrevin, Laurence Faivre, Sandra Fert-Ferrer, Emmanuelle Fourme, Jean-Pierre Fricker, Dany Galliano, Marion Gauthier-Villars, Paul Gesta, Olivier Gilly, Emmanuelle Ginglinger, Stéphanie Gourdon, Sandra Granier, Maud Grelet, Lionel Groussin, Paul Gueguen, Philippe Guilbert, Rosine Guimbaud, Olivia Hentic, Anne Hiebel, Marion Imbert-Bouteille, Olivier Ingster, Bertrand Isidor, Aurélia Jacquette, Anne Jouinot, Sophie Julia, Elodie Lacaze, Emma Lachaier, Aude Laroussinie, Pierre Laurent Puig, Valérie Layet, Lauriane Le Collen, Franck Le Duff, Marine Lebrun, Clémentine Legrand, Bruno Leheup, Marie Lejeune, Sophie Lejeune, Sylvie Leroy, Jean-Marc Limacher, Michel Longy, Véronique Mari, Tanguy Martin-Denavit, Christine Maugard, Diane Moliere, Jessica Moretta, Isabelle Mortemousque, Monique Mozelle-Nivoix, Marie Muller, Gwenaël Nadeau, Sophie Nambot, Jeanne Netter Coti, Tan Dat Nguyen, Catherine Nogues, Sylviane Olschwang, Stéphane Oudard, Nunzia Cinzia Paladino, Jean Pastre, Géraldine Perkins, Clémentine Peyramaure, Emmanuelle Plaisier, Marc Planes, Céline Poirsier, Cornel Popovici, Fabienne Prieur, Pascal Pujol, Margaux Quentel, Amina Radaoui, Hanitra Ranjatoelina Randrianaivo, Manon Reda, Martine Louise Reynaud-Gaubert, Vincent Rigalleau, Axelle Riviere, Julie Robbe, Pauline Rochefort, Laure Rocher, Cécile Rouzier, Sylvie Salenave, Claire Saule, Emmanuelle Simonet-Barouk, Dominique Stoppa Lyonnet, Xavier Tchiknavorian, Constance Thibault, Julie Tinat, Camille Tlemsani, Daniel Toledano, Laurence Venat-Bouvet, Marie-Charlotte Villy, Pauline Vital, Aziz Zaanan, Léonore Zagdoun and Hélène Zattara. We also thank Maud Tusseau for her valuable assistance with data collection.

Funding

This work was supported by a fellowship from the INSERM (Institut National de la Santé et de la Recherche Médicale) to R.V.

Author information

Author notes

  1. Deceased: Maude Vecten.

Authors and Affiliations

  1. Département de Médecine Génomique des Tumeurs et Cancers, Hôpital Européen Georges Pompidou, Fédération de Génétique et de Médecine Génomique, Université Paris Cité, APHP Centre, Paris, France

    Roseline Vibert, Alexandre Buffet, Anne-Paule Gimenez-Roqueplo & Nelly Burnichon

  2. Inserm, Centre de recherche des Cordeliers, Université Paris-Cité, Sorbonne Université, Equipe Labellisée Ligue contre le Cancer, Paris, France

    Roseline Vibert, Alexandre Buffet, Virginie Verkarre, Anne-Paule Gimenez-Roqueplo, Judith Favier & Nelly Burnichon

  3. Aix Marseille Univ, APHM, INSERM, MMG, La Timone University Hospital, Laboratory of Molecular Biology GEnOPé, BIOGENOPOLE, Marseille, France

    Yahya El Baroudi & Anne Barlier

  4. Département de Génétique, Hospices Civils de LYON (HCL), Lyon, France

    Maude Vecten & Sophie Giraud

  5. Réseau National pour Cancers Rares de l’Adulte PREDIR, INCa/APHP, Paris, France

    Maude Vecten, Alexandre Buffet, Virginie Verkarre, Anne-Paule Gimenez-Roqueplo, Stéphane Richard, Sophie Giraud & Nelly Burnichon

  6. Service d’Anatomie et Cytologie Pathologiques, Hôpital Européen Georges Pompidou, Université Paris Cité, APHP Centre, Paris, France

    Virginie Verkarre

  7. Ecole Pratique des Hautes Etudes (EPHE), PSL Université, Paris, France

    Stéphane Richard

  8. Unité d’oncogénétique, Département de Bio-Pathologie, Institut Bergonié, Bordeaux, France

    Sophie Giraud

Authors
  1. Roseline Vibert
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  2. Yahya El Baroudi
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  3. Maude Vecten
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  4. Alexandre Buffet
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  7. Stéphane Richard
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  9. Anne Barlier
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  10. Sophie Giraud
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  11. Nelly Burnichon
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Contributions

Conceptualization: RV, YEB, MV, AlB, VV, A-PG-R, SR, JF, AnB, SG, and NB. Data curation: RV, YEB, MV, SG, and AnB. Formal analysis: RV and NB. Writing—original draft: RV, NB Writing—review and editing: RV, YEB, MV, AlB, VV, A-PG-R, SR, JF, AnB, SG, and NB.

Corresponding author

Correspondence to Roseline Vibert.

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The authors declare no competing interests.

Ethical approval

This study was approved by the APHP Centre Research Ethics Board (IRB #IORG0010044). All patients provided written informed consent for genetic analysis.

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Vibert, R., El Baroudi, Y., Vecten, M. et al. Insights from 2057 germline genetic tests in renal cell carcinoma patients support revisiting testing criteria. Eur J Hum Genet (2026). https://doi.org/10.1038/s41431-025-02006-5

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  • DOI: https://doi.org/10.1038/s41431-025-02006-5

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