An integrative model for the comprehensive classification of BRCA1 and BRCA2 variants of uncertain clinical significance
Abstract Loss-of-function variants in the BRCA1 and BRCA2 susceptibility genes predispose carriers to breast and/or ovarian cancer. The use of germline testing panels containing these genes has grown dramatically, but the interpretation of the results has been complicated by the identification of ma...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-06-01
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| Series: | npj Genomic Medicine |
| Online Access: | https://doi.org/10.1038/s41525-022-00302-3 |
| _version_ | 1818238529980858368 |
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| author | Edwin S. Iversen Gary Lipton Steven N. Hart Kun Y. Lee Chunling Hu Eric C. Polley Tina Pesaran Amal Yussuf Holly LaDuca Elizabeth Chao Rachid Karam David E. Goldgar Fergus J. Couch Alvaro N. A. Monteiro |
| author_facet | Edwin S. Iversen Gary Lipton Steven N. Hart Kun Y. Lee Chunling Hu Eric C. Polley Tina Pesaran Amal Yussuf Holly LaDuca Elizabeth Chao Rachid Karam David E. Goldgar Fergus J. Couch Alvaro N. A. Monteiro |
| author_sort | Edwin S. Iversen |
| collection | DOAJ |
| description | Abstract Loss-of-function variants in the BRCA1 and BRCA2 susceptibility genes predispose carriers to breast and/or ovarian cancer. The use of germline testing panels containing these genes has grown dramatically, but the interpretation of the results has been complicated by the identification of many sequence variants of undefined cancer relevance, termed “Variants of Uncertain Significance (VUS).” We have developed functional assays and a statistical model called VarCall for classifying BRCA1 and BRCA2 VUS. Here we describe a multifactorial extension of VarCall, called VarCall XT, that allows for co–analysis of multiple forms of genetic evidence. We evaluated the accuracy of models defined by the combinations of functional, in silico protein predictors, and family data for VUS classification. VarCall XT classified variants of known pathogenicity status with high sensitivity and specificity, with the functional assays contributing the greatest predictive power. This approach could be used to identify more patients that would benefit from personalized cancer risk assessment and management. |
| first_indexed | 2024-12-12T12:43:07Z |
| format | Article |
| id | doaj.art-a9b402e69faa4cd5a657f04f06fd7feb |
| institution | Directory Open Access Journal |
| issn | 2056-7944 |
| language | English |
| last_indexed | 2024-12-12T12:43:07Z |
| publishDate | 2022-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Genomic Medicine |
| spelling | doaj.art-a9b402e69faa4cd5a657f04f06fd7feb2022-12-22T00:24:11ZengNature Portfolionpj Genomic Medicine2056-79442022-06-01711810.1038/s41525-022-00302-3An integrative model for the comprehensive classification of BRCA1 and BRCA2 variants of uncertain clinical significanceEdwin S. Iversen0Gary Lipton1Steven N. Hart2Kun Y. Lee3Chunling Hu4Eric C. Polley5Tina Pesaran6Amal Yussuf7Holly LaDuca8Elizabeth Chao9Rachid Karam10David E. Goldgar11Fergus J. Couch12Alvaro N. A. Monteiro13Department of Statistical Science, Duke UniversityDepartment of Statistical Science, Duke UniversityDepartment of Health Sciences Research, Mayo ClinicDepartment of Laboratory Medicine and Pathology, Mayo ClinicDepartment of Laboratory Medicine and Pathology, Mayo ClinicDepartment of Laboratory Medicine and Pathology, Mayo ClinicAmbry Genetics CorporationAmbry Genetics CorporationAmbry Genetics CorporationAmbry Genetics CorporationAmbry Genetics CorporationDepartment of Dermatology, University of Utah School of MedicineDepartment of Laboratory Medicine and Pathology, Mayo ClinicCancer Epidemiology Program, H. Lee Moffitt Cancer Center & Research InstituteAbstract Loss-of-function variants in the BRCA1 and BRCA2 susceptibility genes predispose carriers to breast and/or ovarian cancer. The use of germline testing panels containing these genes has grown dramatically, but the interpretation of the results has been complicated by the identification of many sequence variants of undefined cancer relevance, termed “Variants of Uncertain Significance (VUS).” We have developed functional assays and a statistical model called VarCall for classifying BRCA1 and BRCA2 VUS. Here we describe a multifactorial extension of VarCall, called VarCall XT, that allows for co–analysis of multiple forms of genetic evidence. We evaluated the accuracy of models defined by the combinations of functional, in silico protein predictors, and family data for VUS classification. VarCall XT classified variants of known pathogenicity status with high sensitivity and specificity, with the functional assays contributing the greatest predictive power. This approach could be used to identify more patients that would benefit from personalized cancer risk assessment and management.https://doi.org/10.1038/s41525-022-00302-3 |
| spellingShingle | Edwin S. Iversen Gary Lipton Steven N. Hart Kun Y. Lee Chunling Hu Eric C. Polley Tina Pesaran Amal Yussuf Holly LaDuca Elizabeth Chao Rachid Karam David E. Goldgar Fergus J. Couch Alvaro N. A. Monteiro An integrative model for the comprehensive classification of BRCA1 and BRCA2 variants of uncertain clinical significance npj Genomic Medicine |
| title | An integrative model for the comprehensive classification of BRCA1 and BRCA2 variants of uncertain clinical significance |
| title_full | An integrative model for the comprehensive classification of BRCA1 and BRCA2 variants of uncertain clinical significance |
| title_fullStr | An integrative model for the comprehensive classification of BRCA1 and BRCA2 variants of uncertain clinical significance |
| title_full_unstemmed | An integrative model for the comprehensive classification of BRCA1 and BRCA2 variants of uncertain clinical significance |
| title_short | An integrative model for the comprehensive classification of BRCA1 and BRCA2 variants of uncertain clinical significance |
| title_sort | integrative model for the comprehensive classification of brca1 and brca2 variants of uncertain clinical significance |
| url | https://doi.org/10.1038/s41525-022-00302-3 |
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