Comprehensive Analysis And Acmg-Based Classification Ofchek2variants In Hereditary Cancer Patients

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.