학술논문
Functional analysis and clinical classification of 462 germline BRCA2 missense variants affecting the DNA binding domain.
Document Type
Academic Journal
Author
Hu C; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55902, USA.; Huang H; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55902, USA.; Na J; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55902, USA.; Lumby C; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55902, USA.; Abozaid M; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55902, USA.; Holdren MA; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55902, USA.; Rao TJ; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55902, USA.; Karam R; Ambry Genetics, Aliso Viejo, CA 92656, USA.; Pesaran T; Ambry Genetics, Aliso Viejo, CA 92656, USA.; Weyandt JD; Ambry Genetics, Aliso Viejo, CA 92656, USA.; Csuy CM; Ambry Genetics, Aliso Viejo, CA 92656, USA.; Seelaus CA; Ambry Genetics, Aliso Viejo, CA 92656, USA.; Young CC; Ambry Genetics, Aliso Viejo, CA 92656, USA.; Fulk K; Ambry Genetics, Aliso Viejo, CA 92656, USA.; Heidari Z; Ambry Genetics, Aliso Viejo, CA 92656, USA.; Morais Lyra PC Jr; Cancer Epidemiology Program, Moffit Cancer Center, Tampa, FL 33612, USA.; Couch RE; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55902, USA.; Persons B; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55902, USA.; Polley EC; Department of Public Health Sciences, University of Chicago, Chicago, IL 60637, USA.; Gnanaolivu RD; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55902, USA.; Boddicker NJ; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55902, USA.; Monteiro ANA; Cancer Epidemiology Program, Moffit Cancer Center, Tampa, FL 33612, USA.; Yadav S; Department of Medical Oncology, Mayo Clinic, Rochester, MN 55902, USA.; Domchek SM; Division of Hematology Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.; Richardson ME; Ambry Genetics, Aliso Viejo, CA 92656, USA.; Couch FJ; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55902, USA; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55902, USA. Electronic address: couch.fergus@mayo.edu.
Source
Publisher: Cell Press Country of Publication: United States NLM ID: 0370475 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1537-6605 (Electronic) Linking ISSN: 00029297 NLM ISO Abbreviation: Am J Hum Genet Subsets: MEDLINE
Subject
Language
English
Abstract
Variants of uncertain significance (VUSs) in BRCA2 are a common result of hereditary cancer genetic testing. While more than 4,000 unique VUSs, comprised of missense or intronic variants, have been identified in BRCA2, the few missense variants now classified clinically as pathogenic or likely pathogenic are predominantly located in the region encoding the C-terminal DNA binding domain (DBD). We report on functional evaluation of the influence of 462 BRCA2 missense variants affecting the DBD on DNA repair activity of BRCA2 using a homology-directed DNA double-strand break repair assay. Of these, 137 were functionally abnormal, 313 were functionally normal, and 12 demonstrated intermediate function. Comparisons with other functional studies of BRCA2 missense variants yielded strong correlations. Sequence-based in silico prediction models had high sensitivity, but limited specificity, relative to the homology-directed repair assay. Combining the functional results with clinical and genetic data in an American College of Medical Genetics (ACMG)/Association for Molecular Pathology (AMP)-like variant classification framework from a clinical testing laboratory, after excluding known splicing variants and functionally intermediate variants, classified 431 of 442 (97.5%) missense variants (129 as pathogenic/likely pathogenic and 302 as benign/likely benign). Functionally abnormal variants classified as pathogenic by ACMG/AMP rules were associated with a slightly lower risk of breast cancer (odds ratio [OR] 5.15, 95% confidence interval [CI] 3.43-7.83) than BRCA2 DBD protein truncating variants (OR 8.56, 95% CI 6.03-12.36). Overall, functional studies of BRCA2 variants using validated assays substantially improved the variant classification yield from ACMG/AMP models and are expected to improve clinical management of many individuals found to harbor germline BRCA2 missense VUS.
Competing Interests: Declaration of interests R.K., T.P., J.D.W., C.M.C., C.A.S., C.C.Y., K.F., Z.H., and M.E.R. are employees of Ambry Genetics Inc. All other authors declare no competing interests.
(Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Competing Interests: Declaration of interests R.K., T.P., J.D.W., C.M.C., C.A.S., C.C.Y., K.F., Z.H., and M.E.R. are employees of Ambry Genetics Inc. All other authors declare no competing interests.
(Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)