BRCA1 frameshift variants leading to extended incorrect protein C termini.

Autor:	Nepomuceno TC; Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Divisão de Pesquisa Clínica, Instituto Nacional de Câncer, Rio de Janeiro 20230-130, Brazil., Foo TK; Rutgers Cancer Institute of New Jersey and Robert Wood Johnson Medical School, New Brunswick, NJ, USA., Richardson ME; Ambry Genetics, Aliso Viejo, CA, USA., Ranola JMO; Ambry Genetics, Aliso Viejo, CA, USA., Weyandt J; Ambry Genetics, Aliso Viejo, CA, USA., Varga MJ; Ambry Genetics, Aliso Viejo, CA, USA., Alarcon A; Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Gutierrez D; Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., von Wachenfeldt A; Breast Center, Södersjukhuset, Stockholm, Sweden., Eriksson D; Department of Clinical Genetics, Akademiska Sjukhuset, Uppsala, Sweden., Kim R; Bhalwani Familial Cancer Clinic, Princess Margaret Cancer Centre, Toronto, ON M5G 2C1, Canada., Armel S; Bhalwani Familial Cancer Clinic, Princess Margaret Cancer Centre, Toronto, ON M5G 2C1, Canada., Iversen E; Duke University, Durham, NC 27708, USA., Couch FJ; Mayo Clinic, Rochester, MN 55905, USA., Borg Å; University of Lund, 221 00 Lund, Sweden., Xia B; Rutgers Cancer Institute of New Jersey and Robert Wood Johnson Medical School, New Brunswick, NJ, USA., Carvalho MA; Divisão de Pesquisa Clínica, Instituto Nacional de Câncer, Rio de Janeiro 20230-130, Brazil; Instituto Federal do Rio de Janeiro - IFRJ, Rio de Janeiro 20270-021, Brazil. Electronic address: marcelo.carvalho@ifrj.edu.br., Monteiro ANA; Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. Electronic address: alvaro.monteiro@moffitt.org.
Jazyk:	angličtina
Zdroj:	HGG advances [HGG Adv] 2023 Oct 12; Vol. 4 (4), pp. 100240. Date of Electronic Publication: 2023 Sep 16.
DOI:	10.1016/j.xhgg.2023.100240
Abstrakt:	Carriers of BRCA1 germline pathogenic variants are at substantially higher risk of developing breast and ovarian cancer than the general population. Accurate identification of at-risk individuals is crucial for risk stratification and the implementation of targeted preventive and therapeutic interventions. Despite significant progress in variant classification efforts, a sizable portion of reported BRCA1 variants remain as variants of uncertain clinical significance (VUSs). Variants leading to premature protein termination and loss of essential functional domains are typically classified as pathogenic. However, the impact of frameshift variants that result in an extended incorrect terminus is not clear. Using validated functional assays, we conducted a systematic functional assessment of 17 previously reported BRCA1 extended incorrect terminus variants (EITs) and concluded that 16 constitute loss-of-function variants. This suggests that most EITs are likely to be pathogenic. However, one variant, c.5578dup, displayed a protein expression level, affinity to known binding partners, and activity in transcription and homologous recombination assays comparable to the wild-type BRCA1 protein. Twenty-three additional carriers of c.5578dup were identified at a US clinical diagnostic lab and assessed using a family history likelihood model providing, in combination with the functional data, a likely benign interpretation. These results, consistent with family history data in the current study and available data from ClinVar, indicate that most, but not all, BRCA1 variants leading to an extended incorrect terminus constitute loss-of-function variants and underscore the need for comprehensive assessment of individual variants. Competing Interests: Declaration of interests M.E.R., J.M.O.R., J.W., and M.J.V. are full-time, salaried employees of Ambry Genetics. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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