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Comprehensive analysis and ACMG-based classification of CHEK2 variants in Spanish hereditary cancer patients
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  • Gardenia Vargas-Parra,
  • Jesus del Valle,
  • Paula Rofes,
  • Mireia Gausachs,
  • Agostina Stradella,
  • Jose Marcos Moreno-Cabrera,
  • Angela Velasco,
  • Eva Tornero,
  • Mireia Menéndez,
  • Xavier Muñoz,
  • Silvia Iglesias,
  • Adriana Lopez-Doriga,
  • Daniel Azuara,
  • Olga Campos,
  • Raquel Cuesta,
  • Esther Darder,
  • Rafael de Cid,
  • Sara Gonzalez,
  • Alex Teulé,
  • Matilde Navarro,
  • Joan Brunet,
  • Gabriel Capellá,
  • Marta Pineda,
  • Lídia Feliubadaló,
  • Conxi Lázaro
Gardenia Vargas-Parra
Bellvitge Institute for Biomedical Research
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Jesus del Valle
Institut Català d'Oncologia
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Paula Rofes
Institut Catala d' Oncologia
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Mireia Gausachs
Bellvitge Institute for Biomedical Research
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Agostina Stradella
Institut Catala d' Oncologia
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Jose Marcos Moreno-Cabrera
The Institute for Health Science Research Germans Trias i Pujol (IGTP) - PMPPC
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Angela Velasco
Institut Català d'Oncologia-IDIBELL
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Eva Tornero
Institut Català d'Oncologia
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Mireia Menéndez
Institut Català d'Oncologia-IDIBELL
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Xavier Muñoz
Molecular Epidemiology Group, Translational Research Laboratory, Catalan Institute of Oncology-IDIBELL
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Silvia Iglesias
Catalan Institute of Oncology, IDIBELL
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Adriana Lopez-Doriga
Institut d'Investigacions Biomèdiques de Bellvitge (IDIBELL)
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Daniel Azuara
Institut Català d'Oncologia
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Olga Campos
Catalan Institute of Oncology (ICO-IDIBELL)
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Raquel Cuesta
Institut Català d'Oncologia
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Esther Darder
Programa de Consell Genètic en Càncer
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Rafael de Cid
The Institute for Health Science Research Germans Trias i Pujol (IGTP) - PMPPC
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Sara Gonzalez
Instituto Catala d'Oncologia
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Alex Teulé
Institut Català d'Oncologia-IDIBELL
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Matilde Navarro
Catalan Institute of Oncology, IDIBELL
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Joan Brunet
Institut d'Investigació Biomèdica de Girona (IdIBG), Institut Català d'Oncologia, Hospital Josep Trueta
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Gabriel Capellá
ICO-IDIBELL
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Marta Pineda
Institut Català d'Oncologia - IDIBELL
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Lídia Feliubadaló
Catalan Institute of Oncology (ICO-IDIBELL)
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Conxi Lázaro
Catalan Institute of Oncology (ICO)
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Abstract

Background: CHEK2 variants are associated with intermediate breast cancer risk among other cancers. We aimed to comprehensively describe CHEK2 variants in a Spanish hereditary cancer (HC) cohort and adjust American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines for their classification. Methods: First, three CHEK2 frequent variants were screened in a retrospective Hereditary Breast and Ovarian Cancer cohort of 516 patients. After, the whole CHEK2 coding region was analyzed by next-generation sequencing in 1,848 prospective patients with HC suspicion. We refined ACMGAMP criteria and applied different combinatorial rules to classify CHEK2 variants and define risk alleles. Results: We identified 10 CHEK2 null variants, 6 missense variants with discordant interpretation in ClinVar database, and 35 additional variants of unknown significance. Twelve variants were classified as (likely)-pathogenic; 2 can also be considered “established risk-alleles” and one as “likely risk-allele”. The prevalence of (likely)-pathogenic variants in the HC cohort was 0.8% (1.3% in breast cancer patients and 1.0% in hereditary non-polyposis colorectal cancer patients). Conclusions: Here we provide ACMG adjustment guidelines to classify CHEK2 variants. We hope that this work would be useful for variant classification of other genes with low effect variants

Peer review status:ACCEPTED

22 May 2020Submitted to Human Mutation
25 May 2020Submission Checks Completed
25 May 2020Assigned to Editor
10 Jun 2020Reviewer(s) Assigned
23 Jul 2020Review(s) Completed, Editorial Evaluation Pending
26 Jul 2020Editorial Decision: Revise Minor
13 Aug 20201st Revision Received
14 Aug 2020Submission Checks Completed
14 Aug 2020Assigned to Editor
14 Aug 2020Reviewer(s) Assigned
01 Sep 2020Review(s) Completed, Editorial Evaluation Pending
06 Sep 2020Editorial Decision: Accept