Comprehensive analysis and ACMG-based classification ofCHEK2variants in hereditary cancer patients
Por:
Vargas-Parra, G, del Valle, J, Rofes, P, Gausachs, M, Stradella, A, Moreno-Cabrera, JM, Velasco, A, Tornero, E, Menendez, M, Munoz, X, Iglesias, S, Lopez-Doriga, A, Azuara, D, Campos, O, Cuesta, R, Darder, E, de Cid, R, Gonzalez, S, Teule, A, Navarro, M, Brunet, J, Capella, G, Pineda, M, Feliubadalo, L and Lazaro, C
Publicada:
1 dic 2020
Ahead of Print:
1 oct 2020
Resumen:
CHEK2variants are associated with intermediate breast cancer risk, among other cancers. We aimed to comprehensively describeCHEK2variants in a Spanish hereditary cancer (HC) cohort and adjust the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines for their classification. First, threeCHEK2frequent variants were screened in a retrospective Hereditary Breast and Ovarian Cancer cohort of 516 patients. After, the wholeCHEK2coding region was analyzed by next-generation sequencing in 1848 prospective patients with HC suspicion. We refined ACMG-AMP criteria and applied different combined rules to classifyCHEK2variants and define risk alleles. We identified 10CHEK2null variants, 6 missense variants with discordant interpretation in ClinVar database, and 35 additional variants of unknown significance. Twelve variants were classified as (likely)-pathogenic; two 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 nonpolyposis colorectal cancer patients). Here, we provide ACMG adjustment guidelines to classifyCHEK2variants. We hope that this study would be useful for variant classification of other genes with low effect variants.
Filiaciones:
Vargas-Parra, G:
IDIBELL IGTP IDIBGI, Catalan Inst Oncol, Hereditary Canc Program, Badalona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
del Valle, J:
IDIBELL IGTP IDIBGI, Catalan Inst Oncol, Hereditary Canc Program, Badalona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Rofes, P:
IDIBELL IGTP IDIBGI, Catalan Inst Oncol, Hereditary Canc Program, Badalona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Gausachs, M:
IDIBELL IGTP IDIBGI, Catalan Inst Oncol, Hereditary Canc Program, Badalona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
IDIBELL, Catalan Inst Oncol, Dept Med Oncol, Barcelona, Spain
Stradella, A:
IDIBELL IGTP IDIBGI, Catalan Inst Oncol, Hereditary Canc Program, Badalona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
IDIBELL, Catalan Inst Oncol, Dept Med Oncol, Barcelona, Spain
Moreno-Cabrera, JM:
IDIBELL IGTP IDIBGI, Catalan Inst Oncol, Hereditary Canc Program, Badalona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Velasco, A:
IDIBELL IGTP IDIBGI, Catalan Inst Oncol, Hereditary Canc Program, Badalona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Tornero, E:
IDIBELL IGTP IDIBGI, Catalan Inst Oncol, Hereditary Canc Program, Badalona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Menendez, M:
IDIBELL IGTP IDIBGI, Catalan Inst Oncol, Hereditary Canc Program, Badalona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Munoz, X:
IDIBELL IGTP IDIBGI, Catalan Inst Oncol, Hereditary Canc Program, Badalona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Iglesias, S:
IDIBELL IGTP IDIBGI, Catalan Inst Oncol, Hereditary Canc Program, Badalona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Lopez-Doriga, A:
Catalan Inst Oncol, Oncol Data Analyt Program ODAP, Barcelona, Spain
Consortium Biomed Res Epidemiol & Publ Hlth CIBER, Madrid, Spain
Azuara, D:
IDIBELL IGTP IDIBGI, Catalan Inst Oncol, Hereditary Canc Program, Badalona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Campos, O:
IDIBELL IGTP IDIBGI, Catalan Inst Oncol, Hereditary Canc Program, Badalona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Cuesta, R:
IDIBELL IGTP IDIBGI, Catalan Inst Oncol, Hereditary Canc Program, Badalona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Darder, E:
IDIBELL IGTP IDIBGI, Catalan Inst Oncol, Hereditary Canc Program, Badalona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
:
Inst Germans Trias & Pujol PMPPC IGTP, Programa Med Predict & Personalitzada Canc, Genomes Life GCAT Lab Grp, Badalona, Spain
Gonzalez, S:
IDIBELL IGTP IDIBGI, Catalan Inst Oncol, Hereditary Canc Program, Badalona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Teule, A:
IDIBELL IGTP IDIBGI, Catalan Inst Oncol, Hereditary Canc Program, Badalona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Navarro, M:
IDIBELL IGTP IDIBGI, Catalan Inst Oncol, Hereditary Canc Program, Badalona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Brunet, J:
IDIBELL IGTP IDIBGI, Catalan Inst Oncol, Hereditary Canc Program, Badalona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Univ Girona, Sch Med, Dept Med Sci, Girona, Spain
Capella, G:
IDIBELL IGTP IDIBGI, Catalan Inst Oncol, Hereditary Canc Program, Badalona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Pineda, M:
IDIBELL IGTP IDIBGI, Catalan Inst Oncol, Hereditary Canc Program, Badalona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Feliubadalo, L:
IDIBELL IGTP IDIBGI, Catalan Inst Oncol, Hereditary Canc Program, Badalona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Lazaro, C:
IDIBELL IGTP IDIBGI, Catalan Inst Oncol, Hereditary Canc Program, Badalona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
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