ArticleAmerican journal of human genetics2025
Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline PALB2 sequence variants.
Article in American journal of human genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 3 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
3 citing papers in PubMed.
- When splicing is not all or none: GT>GC 5' splice-site variants as a model for intermediate effects and challenges in variant classification.HGG advances · 2026Article
- Integrating enriched case data from national laboratory testing with population-based case-control analyses: a novel statistical likelihood-ratio methodology for PS4 applied to 325,345 breast cancer cases and 671,006 controls.medRxiv : the preprint server for health sciences · 2026Article
- The Performance ofHuman mutation · 2026Article
Corrections and comments
- Erratum issued
Authors and funding
20 authors.
Funding
Abstract
Interpretation of genetic variants is most accurate when gene- and disease-specific considerations are considered. The 2015 ACMG/AMP guidelines form the basis for the application of variant interpretation criteria for Mendelian disorders. The Hereditary Breast, Ovarian, and Pancreatic Cancer Variant Curation Expert Panel (HBOP VCEP) has undertaken the process for creating gene- and disease-specific specifications for the interpretation of PALB2 germline sequence variants. The HBOP VCEP is comprised of experts in the fields of clinical and molecular genetics, epidemiology, functional assays, and variant interpretation. The group met regularly to consider each of the codes from the 2015 ACMG/AMP guidelines to determine their relevance for PALB2. After criteria were created using database analysis, literature review, and expert opinion, they were vetted against a diverse set of pilot variants and ultimately finalized. The HBOP VCEP advised against using 13 codes, limited the use of six codes, and tailored nine codes to create the final PALB2 variant interpretation guidelines. Among the 39 pilot variants, 37 were in ClinVar, and using the new specifications concordant classifications resulted for 31 of the variants (84%). Of the 14 variants of uncertain significance/conflicting variants in ClinVar, four were classified by the VCEP, likely due to code combination modifications and refined population frequency cutoffs. The PALB2-specific guidelines put forward by the HBOP VCEP represent a conservative approach to classifying variants in PALB2 and lead to improved classifications relative to current ClinVar entries. Adoption of these specifications will help to harmonize classifications deposited in the public domain.
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