Germline Missense Variants in <i>BRCA1</i>: New Trends and Challenges for Clinical Annotation
Genetic testing allows for the identification of germline DNA variations, which are associated with a significant increase in the risk of developing breast cancer (BC) and ovarian cancer (OC). Detection of a <i>BRCA1</i> or <i>BRCA2</i> pathogenic variant triggers several cli...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-04-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/4/522 |
| _version_ | 1797766339251666944 |
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| author | Volha A. Golubeva Thales C. Nepomuceno Alvaro N. A. Monteiro |
| author_facet | Volha A. Golubeva Thales C. Nepomuceno Alvaro N. A. Monteiro |
| author_sort | Volha A. Golubeva |
| collection | DOAJ |
| description | Genetic testing allows for the identification of germline DNA variations, which are associated with a significant increase in the risk of developing breast cancer (BC) and ovarian cancer (OC). Detection of a <i>BRCA1</i> or <i>BRCA2</i> pathogenic variant triggers several clinical management actions, which may include increased surveillance and prophylactic surgery for healthy carriers or treatment with the PARP inhibitor therapy for carriers diagnosed with cancer. Thus, standardized validated criteria for the annotation of <i>BRCA1</i> and <i>BRCA2</i> variants according to their pathogenicity are necessary to support clinical decision-making and ensure improved outcomes. Upon detection, variants whose pathogenicity can be inferred by the genetic code are typically classified as pathogenic, likely pathogenic, likely benign, or benign. Variants whose impact on function cannot be directly inferred by the genetic code are labeled as variants of uncertain clinical significance (VUS) and are evaluated by multifactorial likelihood models that use personal and family history of cancer, segregation data, prediction tools, and co-occurrence with a pathogenic <i>BRCA</i> variant. Missense variants, coding alterations that replace a single amino acid residue with another, are a class of variants for which determination of clinical relevance is particularly challenging. Here, we discuss current issues in the missense variant classification by following a typical life cycle of a <i>BRCA1</i> missense variant through detection, annotation and information dissemination. Advances in massively parallel sequencing have led to a substantial increase in VUS findings. Although the comprehensive assessment and classification of missense variants according to their pathogenicity remains the bottleneck, new developments in functional analysis, high throughput assays, data sharing, and statistical models are rapidly changing this scenario. |
| first_indexed | 2024-03-12T20:23:51Z |
| format | Article |
| id | doaj.art-d6e497e83b4d452bb8ae3a7ed06abfde |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T20:23:51Z |
| publishDate | 2019-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-d6e497e83b4d452bb8ae3a7ed06abfde2023-08-02T00:44:27ZengMDPI AGCancers2072-66942019-04-0111452210.3390/cancers11040522cancers11040522Germline Missense Variants in <i>BRCA1</i>: New Trends and Challenges for Clinical AnnotationVolha A. Golubeva0Thales C. Nepomuceno1Alvaro N. A. Monteiro2Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USACancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USACancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USAGenetic testing allows for the identification of germline DNA variations, which are associated with a significant increase in the risk of developing breast cancer (BC) and ovarian cancer (OC). Detection of a <i>BRCA1</i> or <i>BRCA2</i> pathogenic variant triggers several clinical management actions, which may include increased surveillance and prophylactic surgery for healthy carriers or treatment with the PARP inhibitor therapy for carriers diagnosed with cancer. Thus, standardized validated criteria for the annotation of <i>BRCA1</i> and <i>BRCA2</i> variants according to their pathogenicity are necessary to support clinical decision-making and ensure improved outcomes. Upon detection, variants whose pathogenicity can be inferred by the genetic code are typically classified as pathogenic, likely pathogenic, likely benign, or benign. Variants whose impact on function cannot be directly inferred by the genetic code are labeled as variants of uncertain clinical significance (VUS) and are evaluated by multifactorial likelihood models that use personal and family history of cancer, segregation data, prediction tools, and co-occurrence with a pathogenic <i>BRCA</i> variant. Missense variants, coding alterations that replace a single amino acid residue with another, are a class of variants for which determination of clinical relevance is particularly challenging. Here, we discuss current issues in the missense variant classification by following a typical life cycle of a <i>BRCA1</i> missense variant through detection, annotation and information dissemination. Advances in massively parallel sequencing have led to a substantial increase in VUS findings. Although the comprehensive assessment and classification of missense variants according to their pathogenicity remains the bottleneck, new developments in functional analysis, high throughput assays, data sharing, and statistical models are rapidly changing this scenario.https://www.mdpi.com/2072-6694/11/4/522<i>BRCA1</i>variants of uncertain clinical significanceVUSgermline variantshereditary breast and ovarian cancerbreast cancergenetic testingovarian cancervariant classificationclinical annotation |
| spellingShingle | Volha A. Golubeva Thales C. Nepomuceno Alvaro N. A. Monteiro Germline Missense Variants in <i>BRCA1</i>: New Trends and Challenges for Clinical Annotation Cancers <i>BRCA1</i> variants of uncertain clinical significance VUS germline variants hereditary breast and ovarian cancer breast cancer genetic testing ovarian cancer variant classification clinical annotation |
| title | Germline Missense Variants in <i>BRCA1</i>: New Trends and Challenges for Clinical Annotation |
| title_full | Germline Missense Variants in <i>BRCA1</i>: New Trends and Challenges for Clinical Annotation |
| title_fullStr | Germline Missense Variants in <i>BRCA1</i>: New Trends and Challenges for Clinical Annotation |
| title_full_unstemmed | Germline Missense Variants in <i>BRCA1</i>: New Trends and Challenges for Clinical Annotation |
| title_short | Germline Missense Variants in <i>BRCA1</i>: New Trends and Challenges for Clinical Annotation |
| title_sort | germline missense variants in i brca1 i new trends and challenges for clinical annotation |
| topic | <i>BRCA1</i> variants of uncertain clinical significance VUS germline variants hereditary breast and ovarian cancer breast cancer genetic testing ovarian cancer variant classification clinical annotation |
| url | https://www.mdpi.com/2072-6694/11/4/522 |
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