Cargando…
BRCA1 frameshift variants leading to extended incorrect protein C termini
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 interve...
Autores principales: | , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10558845/ https://www.ncbi.nlm.nih.gov/pubmed/37718511 http://dx.doi.org/10.1016/j.xhgg.2023.100240 |
_version_ | 1785117371908751360 |
---|---|
author | Nepomuceno, Thales C. Foo, Tzeh Keong Richardson, Marcy E. Ranola, John Michael O. Weyandt, Jamie Varga, Matthew J. Alarcon, Amaya Gutierrez, Diana von Wachenfeldt, Anna Eriksson, Daniel Kim, Raymond Armel, Susan Iversen, Edwin Couch, Fergus J. Borg, Åke Xia, Bing Carvalho, Marcelo A. Monteiro, Alvaro N.A. |
author_facet | Nepomuceno, Thales C. Foo, Tzeh Keong Richardson, Marcy E. Ranola, John Michael O. Weyandt, Jamie Varga, Matthew J. Alarcon, Amaya Gutierrez, Diana von Wachenfeldt, Anna Eriksson, Daniel Kim, Raymond Armel, Susan Iversen, Edwin Couch, Fergus J. Borg, Åke Xia, Bing Carvalho, Marcelo A. Monteiro, Alvaro N.A. |
author_sort | Nepomuceno, Thales C. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10558845 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-105588452023-10-08 BRCA1 frameshift variants leading to extended incorrect protein C termini Nepomuceno, Thales C. Foo, Tzeh Keong Richardson, Marcy E. Ranola, John Michael O. Weyandt, Jamie Varga, Matthew J. Alarcon, Amaya Gutierrez, Diana von Wachenfeldt, Anna Eriksson, Daniel Kim, Raymond Armel, Susan Iversen, Edwin Couch, Fergus J. Borg, Åke Xia, Bing Carvalho, Marcelo A. Monteiro, Alvaro N.A. HGG Adv Report 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. Elsevier 2023-09-16 /pmc/articles/PMC10558845/ /pubmed/37718511 http://dx.doi.org/10.1016/j.xhgg.2023.100240 Text en © 2023 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Report Nepomuceno, Thales C. Foo, Tzeh Keong Richardson, Marcy E. Ranola, John Michael O. Weyandt, Jamie Varga, Matthew J. Alarcon, Amaya Gutierrez, Diana von Wachenfeldt, Anna Eriksson, Daniel Kim, Raymond Armel, Susan Iversen, Edwin Couch, Fergus J. Borg, Åke Xia, Bing Carvalho, Marcelo A. Monteiro, Alvaro N.A. BRCA1 frameshift variants leading to extended incorrect protein C termini |
title | BRCA1 frameshift variants leading to extended incorrect protein C termini |
title_full | BRCA1 frameshift variants leading to extended incorrect protein C termini |
title_fullStr | BRCA1 frameshift variants leading to extended incorrect protein C termini |
title_full_unstemmed | BRCA1 frameshift variants leading to extended incorrect protein C termini |
title_short | BRCA1 frameshift variants leading to extended incorrect protein C termini |
title_sort | brca1 frameshift variants leading to extended incorrect protein c termini |
topic | Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10558845/ https://www.ncbi.nlm.nih.gov/pubmed/37718511 http://dx.doi.org/10.1016/j.xhgg.2023.100240 |
work_keys_str_mv | AT nepomucenothalesc brca1frameshiftvariantsleadingtoextendedincorrectproteinctermini AT footzehkeong brca1frameshiftvariantsleadingtoextendedincorrectproteinctermini AT richardsonmarcye brca1frameshiftvariantsleadingtoextendedincorrectproteinctermini AT ranolajohnmichaelo brca1frameshiftvariantsleadingtoextendedincorrectproteinctermini AT weyandtjamie brca1frameshiftvariantsleadingtoextendedincorrectproteinctermini AT vargamatthewj brca1frameshiftvariantsleadingtoextendedincorrectproteinctermini AT alarconamaya brca1frameshiftvariantsleadingtoextendedincorrectproteinctermini AT gutierrezdiana brca1frameshiftvariantsleadingtoextendedincorrectproteinctermini AT vonwachenfeldtanna brca1frameshiftvariantsleadingtoextendedincorrectproteinctermini AT erikssondaniel brca1frameshiftvariantsleadingtoextendedincorrectproteinctermini AT kimraymond brca1frameshiftvariantsleadingtoextendedincorrectproteinctermini AT armelsusan brca1frameshiftvariantsleadingtoextendedincorrectproteinctermini AT iversenedwin brca1frameshiftvariantsleadingtoextendedincorrectproteinctermini AT couchfergusj brca1frameshiftvariantsleadingtoextendedincorrectproteinctermini AT borgake brca1frameshiftvariantsleadingtoextendedincorrectproteinctermini AT xiabing brca1frameshiftvariantsleadingtoextendedincorrectproteinctermini AT carvalhomarceloa brca1frameshiftvariantsleadingtoextendedincorrectproteinctermini AT monteiroalvarona brca1frameshiftvariantsleadingtoextendedincorrectproteinctermini |