ArticleGenetics in medicine : official journal of the American College of Medical Genetics2020
Considerations in assessing germline variant pathogenicity using cosegregation analysis.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers, 1 of them a synthesis that pooled it.
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Who cites it
24 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Management of individuals with heterozygous germline pathogenic variants in RAD51C, RAD51D, and BRIP1: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).Genetics in medicine : official journal of the American College of Medical Genetics · 2025Guideline
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- A comprehensive and accessible model for co-segregation analysis in BRCA1, BRCA2, and PALB2 variant classification.Human genetics · 2026Article
- BICEP: an extension to indels and copy number variants for rare variant prioritisation in pedigree analysis.bioRxiv : the preprint server for biology · 2026Article
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- Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline PALB2 sequence variants.American journal of human genetics · 2025Article
- A founder BRCA1 exonic duplication involving breakpoint in T2T reference genome-specific region results in constitutional fusion transcript.NPJ genomic medicine · 2025Article
- Reclassification of VUS inGenetics in medicine open · 2025Article
- Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline ATM sequence variants.American journal of human genetics · 2024Article
- Evidence-based recommendations for gene-specific ACMG/AMP variant classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.American journal of human genetics · 2024Article
- Principles of clinical genetics for rheumatologists: clinical indications and interpretation of broad-based genetic testing.Advances in rheumatology (London, England) · 2024Review
- Atypical cancer risk profile in carriers of Italian founder BRCA1 variant p.His1673del: Implications for classification and clinical management.Cancer medicine · 2024Article
- Specifications of the ACMG/AMP variant curation guidelines for the analysis of germlinemedRxiv : the preprint server for health sciences · 2024Article
- shinyseg: a web application for flexible cosegregation and sensitivity analysis.Bioinformatics (Oxford, England) · 2024Article
- A 39 kb structural variant causing Lynch Syndrome detected by optical genome mapping and nanopore sequencing.European journal of human genetics : EJHG · 2024Article
- Cancer Risks Associated WithJCO precision oncology · 2024Article
- Recommendations for the classification of germline variants in the exonuclease domain of POLE and POLD1.Genome medicine · 2023Article
- Finding significance: New perspectives in variant classification of the RAD51 regulators, BRCA2 and beyond.DNA repair · 2023Review
- A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants: application toHuman mutation · 2023Article
- Article
Corrections and comments
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Authors and funding
5 authors.
Funding
Abstract
purposeThe American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) have developed guidelines for classifying germline variants as pathogenic or benign to interpret genetic testing results. Cosegregation analysis is an important component of the guidelines. There are two main approaches for cosegregation analysis: meiosis counting and Bayes factor-based quantitative methods. Of these, the ACMG/AMP guidelines employ only meiosis counting. The accuracy of either approach has not been sufficiently addressed in previous works.
methodsWe analyzed hypothetical, simulated, and real-life data to evaluate the accuracy of each approach for cancer-associated genes.
resultsWe demonstrate that meiosis counting can provide incorrect classifications when the underlying genetic basis of the disease departs from simple Mendelian situations. Some Bayes factor approaches are currently implemented with inappropriate penetrance. We propose an improved penetrance model and describe several critical considerations, including the accuracy of cosegregation for moderate-risk genes and the impact of pleiotropy, population, and birth year. We highlight a webserver, COOL (Co-segregation Online, http://BJFengLab.org/ ), that implements an accurate Bayes factor cosegregation analysis.
conclusionAn appropriate penetrance model improves the accuracy of Bayes factor cosegregation analysis for high-penetrant variants, and is a better choice than meiosis counting whenever feasible.
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