Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline ATM sequence variants
The ClinGen Hereditary Breast, Ovarian, and Pancreatic Cancer (HBOP) Variant Curation Expert Panel (VCEP) is composed of internationally recognized experts in clinical genetics, molecular biology, and variant interpretation. This VCEP made specifications for the American College of Medical Genetics and Association for Molecular Pathology (ACMG/AMP) guidelines for the ataxia telangiectasia mutated (ATM) gene according to the ClinGen protocol. These gene-specific rules for ATM were modified from the ACMG/AMP guidelines and were tested against 33 ATM variants of various types and classifications in a pilot curation phase. The pilot revealed a majority agreement between the HBOP VCEP classifications and the ClinVar-deposited classifications. Six pilot variants had conflicting interpretations in ClinVar, and re-evaluation with the VCEP's ATM-specific rules resulted in four that were classified as benign, one as likely pathogenic, and one as a variant of uncertain significance (VUS) by the VCEP, improving the certainty of interpretations in the public domain. Overall, 28 of the 33 pilot variants were not VUS, leading to an 85% classification rate. The ClinGen-approved, modified rules demonstrated value for improved interpretation of variants in ATM.
Authors
- Logan C. Walker (ORCID: https://orcid.org/0000-0003-0018-3719)
- Katherine R. Schon (ORCID: https://orcid.org/0000-0001-8054-8954)
- Lauren Zec
- Fergus J. Couch (ORCID: https://orcid.org/0000-0001-9417-9985)
- Colin C. Young (ORCID: https://orcid.org/0000-0002-9385-8262)
- Clare Turnbull (ORCID: https://orcid.org/0000-0002-1734-5772)
- William D. Foulkes (ORCID: https://orcid.org/0000-0001-7427-4651)
- Marcy E. Richardson (ORCID: https://orcid.org/0000-0002-4626-4920)
- Tina Pesaran (ORCID: https://orcid.org/0000-0001-9807-4304)
- Miguel de la Hoya (ORCID: https://orcid.org/0000-0002-8113-1410)
- Marc Tischkowitz (ORCID: https://orcid.org/0000-0002-7880-0628)
- Melissa Cline (ORCID: https://orcid.org/0000-0002-0148-1956)
- Sean V. Tavtigian (ORCID: https://orcid.org/0000-0002-7543-8221)
- Terra Brannan
- Michael J. Anderson (ORCID: https://orcid.org/0000-0003-1393-3590)
- Shannon McNulty (ORCID: https://orcid.org/0000-0002-0566-4629)
- Susan Hiraki (ORCID: https://orcid.org/0000-0001-9799-2402)
- Álvaro N.A. Monteiro (ORCID: https://orcid.org/0000-0002-8448-4801)
- Megan Holdren
- Amanda B. Spurdle (ORCID: https://orcid.org/0000-0003-1337-7897)
- Thomas Slavin
Institutions
- University of North Carolina at Chapel Hill (US)
- Mayo Clinic (US)
- Institute of Cancer Research (GB)
- University of California, Santa Cruz (US)
- QIMR Berghofer Medical Research Institute (AU)
- University of Utah (US)
- Huntsman Cancer Institute (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)
- City of Hope (US)
- McGill Genome Centre (CA)
- Natera (United States) (US)
- Mayo Clinic in Arizona (US)
- Mayo Clinic in Florida (US)
- Ambry Genetics (United States) (US)
- Invitae (United States) (US)
- NIHR Cambridge Biomedical Research Centre (GB)
- McGill University (CA)
- University of Otago (NZ)
Publication Details
- Journal
- The American Journal of Human Genetics
- Published
- 2024-09-23
- DOI
- https://doi.org/10.1016/j.ajhg.2024.08.022
- Citations
- 12
- Primary Topic
- Genomics and Rare Diseases
- Type
- article
- Field-Weighted Citation Impact
- 6.60
Funders
- Breast Cancer Research Foundation
- Cancer Research UK
- National Institute for Health and Care Research
- European Commission
- Ministry of Science and Innovation, New Zealand
- 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