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BRCA1 frameshift va...
BRCA1 frameshift variants leading to extended incorrect protein C termini
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- Nepomuceno, Thales C. (author)
- H. Lee Moffitt Cancer Center & Research Institute
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- Keong Foo, Tzeh (author)
- Rutgers Cancer Institute of New Jersey
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- Richardson, Marcy E. (author)
- Ambry Genetics Corporation
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- Ranola, John Michael O. (author)
- Ambry Genetics Corporation
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- Weyandt, Jamie (author)
- Ambry Genetics Corporation
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- Varga, Matthew J. (author)
- Ambry Genetics Corporation
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- Alarcon, Amaya (author)
- H. Lee Moffitt Cancer Center & Research Institute,INCA Brazilian National Cancer Institute
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- Gutierrez, Diana (author)
- H. Lee Moffitt Cancer Center & Research Institute
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- von Wachenfeldt, Anna (author)
- Stockholm South General Hospital
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- Eriksson, Daniel (author)
- Department of Clinical Genetics, Akademiska Sjukhuset, Uppsala, Sweden,Uppsala University Hospital
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- Kim, Raymond (author)
- Princess Margaret Hospital University of Toronto
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- Armel, Susan (author)
- Princess Margaret Hospital University of Toronto
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- Iversen, Edwin (author)
- Duke University
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- Couch, Fergus J. (author)
- Mayo Clinic Minnesota
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- Borg, Åke (author)
- Lund University,Lunds universitet,Bröstcancer-genetik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Familjär bröstcancer,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Breastcancer-genetics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,Familial Breast Cancer,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Xia, Bing (author)
- Rutgers Cancer Institute of New Jersey
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Carvalho, Marcelo A. (author)
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Monteiro, Alvaro N. A. (author)
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H Lee Moffitt Cancer Center & Research Institute Rutgers Cancer Institute of New Jersey (creator_code:org_t)
- Elsevier, 2023
- 2023
- English.
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In: Human Genetics and Genomics Advances. - : Elsevier. - 2666-2477. ; 4:4
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
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- ref (subject category)
- art (subject category)
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- By the author/editor
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Nepomuceno, Thal ...
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Keong Foo, Tzeh
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Richardson, Marc ...
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Ranola, John Mic ...
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Weyandt, Jamie
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Varga, Matthew J ...
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show more...
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Alarcon, Amaya
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Gutierrez, Diana
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von Wachenfeldt, ...
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Eriksson, Daniel
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Kim, Raymond
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Armel, Susan
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Iversen, Edwin
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Couch, Fergus J.
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Borg, Åke
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Xia, Bing
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Carvalho, Marcel ...
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Monteiro, Alvaro ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medical Genetics
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
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Human Genetics a ...
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Uppsala University
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Lund University