ArticleAmerican journal of human genetics2016
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.
Article in American journal of human genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 79 papers.
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79 citing papers in PubMed, 132 citations in OpenAlex.
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- Secondary Findings from Exome Sequencing of a Greek Cohort.Current issues in molecular biology · 2025Article
- Predicting Pathogenic Variants of Breast Cancer Using Ultrasound-Derived Machine Learning Models.Cancers · 2025Article
- Analysis of TSC1 and TSC2 genes and evaluation of phenotypic correlations with tuberous sclerosis.Molecular genetics and genomics : MGG · 2024Article
- A missense variant effect map for the human tumor-suppressor protein CHK2.American journal of human genetics · 2024Article
- Universal genetic counseling in breast cancer patients significantly improves overall testing rates and improves completion rates in subpopulations.Breast cancer research and treatment · 2024Article
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- Quality assurance within the context of genome diagnostics (a german perspective).Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2023Article
- Multiple Germline Events Contribute to Cancer Development in Patients with Li-Fraumeni Syndrome.Cancer research communications · 2023Article
- Comprehensive clinical characterization of patients withAnnals of surgical treatment and research · 2022Article
- Comprehensive genetic testing approaches as the basis for personalized management of growth disturbances: current status and perspectives.Endocrine connections · 2022Review
- BRCA1 Norway: comparison of classification for BRCA1 germline variants detected in families with suspected hereditary breast and ovarian cancer between different laboratories.Familial cancer · 2022Article
- Machine-learning of complex evolutionary signals improves classification of SNVs.NAR genomics and bioinformatics · 2022Article
19 more citing papers are in PubMed but not listed here.
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Authors and funding
20 authors at 9 institutions in 2 countries.
Funding
Abstract
Sequencing tests assaying panels of genes or whole exomes are widely available for cancer risk evaluation. However, methods for classification of variants resulting from this testing are not well studied. We evaluated the ability of a variant-classification methodology based on American College of Medical Genetics and Genomics (ACMG) guidelines to define the rate of mutations and variants of uncertain significance (VUS) in 180 medically relevant genes, including all ACMG-designated reportable cancer and non-cancer-associated genes, in individuals who met guidelines for hereditary cancer risk evaluation. We performed whole-exome sequencing in 404 individuals in 253 families and classified 1,640 variants. Potentially clinically actionable (likely pathogenic [LP] or pathogenic [P]) versus nonactionable (VUS, likely benign, or benign) calls were 95% concordant with locus-specific databases and Clinvar. LP or P mutations were identified in 12 of 25 breast cancer susceptibility genes in 26 families without identified BRCA1/2 mutations (11%). Evaluation of 84 additional genes associated with autosomal-dominant cancer susceptibility identified LP or P mutations in only two additional families (0.8%). However, individuals from 10 of 253 families (3.9%) had incidental LP or P mutations in 32 non-cancer-associated genes, and 9% of individuals were monoallelic carriers of a rare LP or P mutation in 39 genes associated with autosomal-recessive cancer susceptibility. Furthermore, 95% of individuals had at least one VUS. In summary, these data support the clinical utility of ACMG variant-classification guidelines. Additionally, evaluation of extended panels of cancer-associated genes in breast/ovarian cancer families leads to only an incremental clinical benefit but substantially increases the complexity of the results.
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