ArticleGenome medicine2023
Recommendations for the classification of germline variants in the exonuclease domain of POLE and POLD1.
Article in Genome medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 19 citations in OpenAlex.
- Integrating germline and tumor sequencing to improve hereditary cancer diagnosis and care.European journal of human genetics : EJHG · 2026Review
- Interpreting the effects of DNA polymerase variants at the structural level.Molecular oncology · 2026Article
- Genotype-phenotype heterogeneity among patients with lipodystrophy harboring rare POLD1 variants.The Journal of clinical endocrinology and metabolism · 2026Article
- Genome Sequencing of Undiagnosed European Patients Suspected of Hereditary Cancer: Diagnostic Yield and Identification of Candidate Causative Variants.JCO precision oncology · 2026Article
- Decoding Immunotherapy Response in Colorectal Cancer: Translational Insights Beyond MSI.Cancers · 2026Review
- Functional Characterization ofDiseases (Basel, Switzerland) · 2026Article
- Hereditary Endometrial Cancer: Lynch Syndrome, Mismatch Repair Deficiency, and Emerging Genetic Predispositions-A Comprehensive Review with Clinical and Laboratory Guidelines.International journal of molecular sciences · 2026Review
- Germline pathogenic variants detected by GenMineTOP: insight from a nationwide tumor/normal paired comprehensive genomic profiling test, in Japan.Journal of human genetics · 2026Article
- Inborn errors of immunity with DNA repair disorders: at the interface of immune deficiency, immune dysregulation, and malignancy.Frontiers in immunology · 2026Review
- The germline POLD1 c.1420 C > A (p.Leu474Ile) variant segregates with endometrial cancer, colorectal cancer and colonic polyps demonstrating hypermutation and defective POLD1 mutational signatures.Familial cancer · 2025Article
- Genetics, genomics and clinical features of adenomatous polyposis.Familial cancer · 2025Review
- PolED: a manually curated database of functional studies of POLE and POLD1 variants reported in humans.Database : the journal of biological databases and curation · 2025Article
- Review
- Case Report: Expansion of theFrontiers in oncology · 2025Article
- Review
- Discovery of recessive effect of human polymerase δ proofreading deficiency through mutational analysis of POLD1-mutated normal and cancer cells.European journal of human genetics : EJHG · 2024Article
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Authors and funding
10 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundGermline variants affecting the proofreading activity of polymerases epsilon and delta cause a hereditary cancer and adenomatous polyposis syndrome characterized by tumors with a high mutational burden and a specific mutational spectrum. In addition to the implementation of multiple pieces of evidence for the classification of gene variants, POLE and POLD1 variant classification is particularly challenging given that non-disruptive variants affecting the proofreading activity of the corresponding polymerase are the ones associated with cancer. In response to an evident need in the field, we have developed gene-specific variant classification recommendations, based on the ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) criteria, for the assessment of non-disruptive variants located in the sequence coding for the exonuclease domain of the polymerases.
methodsA training set of 23 variants considered pathogenic or benign was used to define the usability and strength of the ACMG/AMP criteria. Population frequencies, computational predictions, co-segregation data, phenotypic and tumor data, and functional results, among other features, were considered.
resultsGene-specific variant classification recommendations for non-disruptive variants located in the exonuclease domain of POLE and POLD1 were defined. The resulting recommendations were applied to 128 exonuclease domain variants reported in the literature and/or public databases. A total of 17 variants were classified as pathogenic or likely pathogenic, and 17 as benign or likely benign.
conclusionsOur recommendations, with room for improvement in the coming years as more information become available on carrier families, tumor molecular characteristics and functional assays, are intended to serve the clinical and scientific communities and help improve diagnostic performance, avoiding variant misclassifications.
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