Evidence-based recommendations for gene-specific ACMG/AMP variant classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel

Michael T. Parsons,Miguel de la Hoya, Marcy E. Richardson,Emma Tudini,Michael Anderson, Windy Berkofsky-Fessler,Sandrine M. Caputo, Raymond C. Chan,Melissa C. Cline,Bing-Jian Feng,Cristina Fortuno,Encarna Gomez-Garcia, Johanna Hadler, Susan Hiraki, Megan Holdren,Claude Houdayer, Kathleen Hruska,Paul James,Rachid Karam,Huei San Leong,Alexandra Martins,Arjen R. Mensenkamp,Alvaro N. Monteiro,Vaishnavi Nathan, Robert O’Connor,Inge Sokilde Pedersen,Tina Pesaran,Paolo Radice, Gunnar Schmidt,Melissa Southey,Sean Tavtigian,Bryony A. Thompson,Amanda E. Toland,Clare Turnbull, Maartje J. Vogel, Jamie Weyandt,George A.R. Wiggins, Lauren Zec,Fergus J. Couch,Logan C. Walker,Maaike P. G. Vreeswijk,David E. Goldgar,Amanda B. Spurdle

medrxiv（2024）

引用 0|浏览20

暂无评分

摘要

The ENIGMA research consortium () develops and applies methods to determine clinical significance of variants in Hereditary Breast and Ovarian Cancer genes. An ENIGMA BRCA1/2 classification sub-group, originally formed in 2016 as a ClinGen external expert panel, evolved into a ClinGen internal Variant Curation Expert Panel (VCEP) to align with Federal Drug Administration recognized processes for ClinVar contributions. The VCEP reviewed American College of Medical Genetics/Association of Molecular Pathology (ACMG/AMP) classification criteria for relevance to interpreting BRCA1 and BRCA2 variants. Statistical methods were used to calibrate evidence strength for different data types. Pilot specifications were tested on 40 variants, and documentation revised for clarity and ease-of-use. The original criterion descriptions for 13 evidence codes were considered non-applicable or overlapping with other criteria. Scenario of use was extended or re-purposed for eight codes. Extensive analysis and/or data review informed specification descriptions and weights for all codes. Specifications were applied to pilot variants with pre-existing ClinVar classification as follows: 13 Uncertain Significance or Conflicting, 14 Pathogenic and/or Likely Pathogenic, and 13 Benign and/or Likely Benign. Review resolved classification for 11/13 Uncertain Significance or Conflicting variants, and retained or improved confidence in classification for the remaining variants. Alignment of pre-existing ENIGMA research classification processes with ACMG/AMP classification guidelines highlighted several gaps in both the research processes and the baseline ACMG/AMP criteria. Calibration of evidence types was key to justify utility and strength of different evidence types for gene-specific application. The gene-specific criteria demonstrated value for improving ACMG/AMP-aligned classification of BRCA1 and BRCA2 variants. ### Competing Interest Statement M.A. was a paid employee of Invitae. R.C.C. and R.O. are paid employees of Color Health. M.E.R., T.P. and R.K. are paid employees of Ambry Genetics. A.R.M. and M.J.V. received funds from AstraZeneca for contribution to sponsored quality assessments and variant interpretation of BRCA1 and BRCA2 VUS (funds paid to the institution). ### Funding Statement The work of M.T.P. was supported in part by National Institutes of Health grant U24 5U24CA258058-02. M.C. was supported by the Basser Center for BRCA Research and the National Cancer Institute (U24CA258058). F.J.C. was supported by NIH grants U24CA258058, R35CA253187 and P50CA116201 and the Breast Cancer Research Foundation. M.d.l.H. was supported by a grant from the Spanish Ministry of Science and Innovation, Plan Nacional de I+D+I 2013-2016, ISCIII (PI20/00110) co-funded by FEDER from Regional Development European Funds (European Union) and by NIH grant 5U24CA258058-02. M.H. was supported by NIH grant 5U24CA258058. A.N.M. is a Breast Cancer Research Foundation investigator. P.R. was supported by a grant of the Italian Association for Cancer Research (AIRC - IG 22093). M.S. was supported by an Australian National Health and Medical Research Council L3 Investigator Grant (GNT2017325). M.P.G.V was supported by The Dutch Cancer Society grant KWF 12754. L.C.W. and G.A.R.W. were supported by the New Zealand Health Research Council (22/187). Cristina Fortuno was supported in part by NHMRC project funding (APP1161589), and a grant from the National Breast Cancer Foundation, Australia (IIRS-21-102). ABS was supported by an NHMRC Investigator Fellowship (APP177524). U24CA258058 for in-part support of VCEP activities from 2023. C.T. acknowledges funding from a Cancer Research UK catalyst award (C61296/A27223). This publication was supported in part by the National Institute of General Medical Sciences R01 GM134731 and Department of Defense W81XWH1810269. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Human Research Ethics Committee of QIMR Berghofer Medical Research Institute gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript

查看译文

AI 理解论文

溯源树

样例

生成溯源树，研究论文发展脉络

Chat Paper

正在生成论文摘要