Comprehensive analysis and ACMG-based classification of CHEK2 variants in hereditary cancer patients.

Base Sequence Checkpoint Kinase 2 / genetics Cohort Studies DNA Copy Number Variations / genetics Family Female Gene Expression Regulation Genetic Variation Humans Male Molecular Sequence Annotation Mutation / genetics Neoplasms / genetics Pedigree RNA Splice Sites / genetics RNA, Messenger / genetics Societies, Scientific

CHEK2 hereditary cancer low penetrance molecular diagnosis risk allele variant classification

Journal

Human mutation

ISSN: 1098-1004

Titre abrégé: Hum Mutat

Pays: United States

ID NLM: 9215429

Informations de publication

Date de publication:
12 2020

Historique:

received: 22 05 2020

revised: 13 08 2020

accepted: 06 09 2020

pubmed: 10 9 2020

medline: 26 11 2021

entrez: 9 9 2020

Statut: ppublish

Résumé

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 the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines for their classification. 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 1848 prospective patients with HC suspicion. We refined ACMG-AMP criteria and applied different combined rules to classify CHEK2 variants and define risk alleles. 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; 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 classify CHEK2 variants. We hope that this study would be useful for variant classification of other genes with low effect variants.

Identifiants

DOI: 10.1002/humu.24110 PMID: 32906215

pubmed: 32906215

doi: 10.1002/humu.24110

doi:

Substances chimiques

RNA Splice Sites 0

RNA, Messenger 0

Checkpoint Kinase 2 EC 2.7.1.11

CHEK2 protein, human EC 2.7.11.1

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

2128-2142

Informations de copyright

Références

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