Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline PALB2 sequence variants

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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Publication Details

Journal
The American Journal of Human Genetics
Published
2025-09-17
DOI
https://doi.org/10.1016/j.ajhg.2025.08.020
Citations
1
Primary Topic
Genomics and Rare Diseases
Type
article
Field-Weighted Citation Impact
1.82

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article

Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline PALB2 sequence variants

Logan C. Walker, Lauren Zec, Fergus J. Couch, Colin C. Young et al.
1 citations
The American Journal of Human Genetics
Genomics and Rare Diseases
1.82
article

Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline PALB2 sequence variants

Logan C. Walker, Lauren Zec, Fergus J. Couch, Colin C. Young, Clare Turnbull, William D. Foulkes, Marcy E. Richardson, Tina Pesaran, Martin J. Bishop, Miguel de la Hoya, Marc Tischkowitz, Sean V. Tavtigian, Terra Brannan, Shannon McNulty, Susan Hiraki, Álvaro N.A. Monteiro, Kara Anne Bernstein, Jean‐Yves Masson, Megan Holdren, Amanda B. Spurdle
article en
1 citations

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.

The American Journal of Human GeneticsVol. 112(10)
University of North Carolina at Chapel Hill (US), Mayo Clinic (US), Institute of Cancer Research (GB), QIMR Berghofer Medical Research Institute (AU), University of Utah (US), Hospital Clínico San Carlos (ES), Moffitt Cancer Center (US), National Institute for Health and Care Research (GB), Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (ES), McGill Genome Centre (CA), Natera (United States) (US), Mayo Clinic in Arizona (US), Mayo Clinic in Florida (US), Ambry Genetics (United States) (US), Université Laval (CA), McGill University (CA), University of Pennsylvania (US), University of Otago (NZ)
Breast Cancer Research Foundation, Cancer Research UK, National Institute for Health and Care Research, Ministerio de Ciencia e Innovación, National Institutes of Health, Canadian Institutes of Health Research, National Health and Medical Research Council, Instituto de Salud Carlos III, NIHR Cambridge Biomedical Research Centre, Congressionally Directed Medical Research Programs
Openalex Percentile: Top 13%
Genomics and Rare Diseases
1.82
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