GFP-Fragment Reassembly Screens for the Functional Characterization of Variants of Uncertain Significance in Protein Interaction Domains of the <i<BRCA1</i< and <i<BRCA2</i< Genes

Genetic testing for <i<BRCA1</i< and <i<BRCA2</i< genes has led to the identification of many unique variants of uncertain significance (VUS). Multifactorial likelihood models that predict the odds ratio for VUS in favor or against cancer causality, have been developed, but t...
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Gespeichert in:

Autor*in:	Laura Caleca [verfasserIn] Mara Colombo [verfasserIn] Thomas van Overeem Hansen [verfasserIn] Conxi Lázaro [verfasserIn] Siranoush Manoukian [verfasserIn] Michael T. Parsons [verfasserIn] Amanda B. Spurdle [verfasserIn] Paolo Radice [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2019

Schlagwörter:	hereditary breast/ovarian cancer variant of uncertain significance functional assays protein-protein interaction

Übergeordnetes Werk:	In: Cancers - MDPI AG, 2010, 11(2019), 2, p 151
Übergeordnetes Werk:	volume:11 ; year:2019 ; number:2, p 151

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/cancers11020151

Katalog-ID:	DOAJ005964776

Internformat


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allfields	10.3390/cancers11020151 doi (DE-627)DOAJ005964776 (DE-599)DOAJ519c2b8ac25f4107a3c3dc723108577a DE-627 ger DE-627 rakwb eng RC254-282 Laura Caleca verfasserin aut GFP-Fragment Reassembly Screens for the Functional Characterization of Variants of Uncertain Significance in Protein Interaction Domains of the <i<BRCA1</i< and <i<BRCA2</i< Genes 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Genetic testing for <i<BRCA1</i< and <i<BRCA2</i< genes has led to the identification of many unique variants of uncertain significance (VUS). Multifactorial likelihood models that predict the odds ratio for VUS in favor or against cancer causality, have been developed, but their use is conditioned by the amount of necessary data, which are difficult to obtain if a variant is rare. As an alternative, variants mapping to the coding regions can be examined using in vitro functional assays. BRCA1 and BRCA2 proteins promote genome protection by interacting with different proteins. In this study, we assessed the functional effect of two sets of variants in <i<BRCA</i< genes by exploiting the green fluorescent protein (GFP)-reassembly in vitro assay, which was set-up to test the BRCA1/BARD1, BRCA1/UbcH5a, and BRCA2/DSS1 interactions. Based on the findings observed for the validation panels of previously classified variants, BRCA1/UbcH5a and BRCA2/DSS1 binding assays showed 100% sensitivity and specificity in identifying pathogenic and non-pathogenic variants. While the actual efficiency of these assays in assessing the clinical significance of BRCA VUS has to be verified using larger validation panels, our results suggest that the GFP-reassembly assay is a robust method to identify variants affecting normal protein functioning and contributes to the classification of VUS. hereditary breast/ovarian cancer <i<BRCA1</i< <i<BRCA2</i< variant of uncertain significance functional assays protein-protein interaction Neoplasms. Tumors. Oncology. Including cancer and carcinogens Mara Colombo verfasserin aut Thomas van Overeem Hansen verfasserin aut Conxi Lázaro verfasserin aut Siranoush Manoukian verfasserin aut Michael T. Parsons verfasserin aut Amanda B. Spurdle verfasserin aut Paolo Radice verfasserin aut In Cancers MDPI AG, 2010 11(2019), 2, p 151 (DE-627)614095670 (DE-600)2527080-1 20726694 nnns volume:11 year:2019 number:2, p 151 https://doi.org/10.3390/cancers11020151 kostenfrei https://doaj.org/article/519c2b8ac25f4107a3c3dc723108577a kostenfrei https://www.mdpi.com/2072-6694/11/2/151 kostenfrei https://doaj.org/toc/2072-6694 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2019 2, p 151
spelling	10.3390/cancers11020151 doi (DE-627)DOAJ005964776 (DE-599)DOAJ519c2b8ac25f4107a3c3dc723108577a DE-627 ger DE-627 rakwb eng RC254-282 Laura Caleca verfasserin aut GFP-Fragment Reassembly Screens for the Functional Characterization of Variants of Uncertain Significance in Protein Interaction Domains of the <i<BRCA1</i< and <i<BRCA2</i< Genes 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Genetic testing for <i<BRCA1</i< and <i<BRCA2</i< genes has led to the identification of many unique variants of uncertain significance (VUS). Multifactorial likelihood models that predict the odds ratio for VUS in favor or against cancer causality, have been developed, but their use is conditioned by the amount of necessary data, which are difficult to obtain if a variant is rare. As an alternative, variants mapping to the coding regions can be examined using in vitro functional assays. BRCA1 and BRCA2 proteins promote genome protection by interacting with different proteins. In this study, we assessed the functional effect of two sets of variants in <i<BRCA</i< genes by exploiting the green fluorescent protein (GFP)-reassembly in vitro assay, which was set-up to test the BRCA1/BARD1, BRCA1/UbcH5a, and BRCA2/DSS1 interactions. Based on the findings observed for the validation panels of previously classified variants, BRCA1/UbcH5a and BRCA2/DSS1 binding assays showed 100% sensitivity and specificity in identifying pathogenic and non-pathogenic variants. While the actual efficiency of these assays in assessing the clinical significance of BRCA VUS has to be verified using larger validation panels, our results suggest that the GFP-reassembly assay is a robust method to identify variants affecting normal protein functioning and contributes to the classification of VUS. hereditary breast/ovarian cancer <i<BRCA1</i< <i<BRCA2</i< variant of uncertain significance functional assays protein-protein interaction Neoplasms. Tumors. Oncology. Including cancer and carcinogens Mara Colombo verfasserin aut Thomas van Overeem Hansen verfasserin aut Conxi Lázaro verfasserin aut Siranoush Manoukian verfasserin aut Michael T. Parsons verfasserin aut Amanda B. Spurdle verfasserin aut Paolo Radice verfasserin aut In Cancers MDPI AG, 2010 11(2019), 2, p 151 (DE-627)614095670 (DE-600)2527080-1 20726694 nnns volume:11 year:2019 number:2, p 151 https://doi.org/10.3390/cancers11020151 kostenfrei https://doaj.org/article/519c2b8ac25f4107a3c3dc723108577a kostenfrei https://www.mdpi.com/2072-6694/11/2/151 kostenfrei https://doaj.org/toc/2072-6694 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2019 2, p 151
allfields_unstemmed	10.3390/cancers11020151 doi (DE-627)DOAJ005964776 (DE-599)DOAJ519c2b8ac25f4107a3c3dc723108577a DE-627 ger DE-627 rakwb eng RC254-282 Laura Caleca verfasserin aut GFP-Fragment Reassembly Screens for the Functional Characterization of Variants of Uncertain Significance in Protein Interaction Domains of the <i<BRCA1</i< and <i<BRCA2</i< Genes 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Genetic testing for <i<BRCA1</i< and <i<BRCA2</i< genes has led to the identification of many unique variants of uncertain significance (VUS). Multifactorial likelihood models that predict the odds ratio for VUS in favor or against cancer causality, have been developed, but their use is conditioned by the amount of necessary data, which are difficult to obtain if a variant is rare. As an alternative, variants mapping to the coding regions can be examined using in vitro functional assays. BRCA1 and BRCA2 proteins promote genome protection by interacting with different proteins. In this study, we assessed the functional effect of two sets of variants in <i<BRCA</i< genes by exploiting the green fluorescent protein (GFP)-reassembly in vitro assay, which was set-up to test the BRCA1/BARD1, BRCA1/UbcH5a, and BRCA2/DSS1 interactions. Based on the findings observed for the validation panels of previously classified variants, BRCA1/UbcH5a and BRCA2/DSS1 binding assays showed 100% sensitivity and specificity in identifying pathogenic and non-pathogenic variants. While the actual efficiency of these assays in assessing the clinical significance of BRCA VUS has to be verified using larger validation panels, our results suggest that the GFP-reassembly assay is a robust method to identify variants affecting normal protein functioning and contributes to the classification of VUS. hereditary breast/ovarian cancer <i<BRCA1</i< <i<BRCA2</i< variant of uncertain significance functional assays protein-protein interaction Neoplasms. Tumors. Oncology. Including cancer and carcinogens Mara Colombo verfasserin aut Thomas van Overeem Hansen verfasserin aut Conxi Lázaro verfasserin aut Siranoush Manoukian verfasserin aut Michael T. Parsons verfasserin aut Amanda B. Spurdle verfasserin aut Paolo Radice verfasserin aut In Cancers MDPI AG, 2010 11(2019), 2, p 151 (DE-627)614095670 (DE-600)2527080-1 20726694 nnns volume:11 year:2019 number:2, p 151 https://doi.org/10.3390/cancers11020151 kostenfrei https://doaj.org/article/519c2b8ac25f4107a3c3dc723108577a kostenfrei https://www.mdpi.com/2072-6694/11/2/151 kostenfrei https://doaj.org/toc/2072-6694 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2019 2, p 151
allfieldsGer	10.3390/cancers11020151 doi (DE-627)DOAJ005964776 (DE-599)DOAJ519c2b8ac25f4107a3c3dc723108577a DE-627 ger DE-627 rakwb eng RC254-282 Laura Caleca verfasserin aut GFP-Fragment Reassembly Screens for the Functional Characterization of Variants of Uncertain Significance in Protein Interaction Domains of the <i<BRCA1</i< and <i<BRCA2</i< Genes 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Genetic testing for <i<BRCA1</i< and <i<BRCA2</i< genes has led to the identification of many unique variants of uncertain significance (VUS). Multifactorial likelihood models that predict the odds ratio for VUS in favor or against cancer causality, have been developed, but their use is conditioned by the amount of necessary data, which are difficult to obtain if a variant is rare. As an alternative, variants mapping to the coding regions can be examined using in vitro functional assays. BRCA1 and BRCA2 proteins promote genome protection by interacting with different proteins. In this study, we assessed the functional effect of two sets of variants in <i<BRCA</i< genes by exploiting the green fluorescent protein (GFP)-reassembly in vitro assay, which was set-up to test the BRCA1/BARD1, BRCA1/UbcH5a, and BRCA2/DSS1 interactions. Based on the findings observed for the validation panels of previously classified variants, BRCA1/UbcH5a and BRCA2/DSS1 binding assays showed 100% sensitivity and specificity in identifying pathogenic and non-pathogenic variants. While the actual efficiency of these assays in assessing the clinical significance of BRCA VUS has to be verified using larger validation panels, our results suggest that the GFP-reassembly assay is a robust method to identify variants affecting normal protein functioning and contributes to the classification of VUS. hereditary breast/ovarian cancer <i<BRCA1</i< <i<BRCA2</i< variant of uncertain significance functional assays protein-protein interaction Neoplasms. Tumors. Oncology. Including cancer and carcinogens Mara Colombo verfasserin aut Thomas van Overeem Hansen verfasserin aut Conxi Lázaro verfasserin aut Siranoush Manoukian verfasserin aut Michael T. Parsons verfasserin aut Amanda B. Spurdle verfasserin aut Paolo Radice verfasserin aut In Cancers MDPI AG, 2010 11(2019), 2, p 151 (DE-627)614095670 (DE-600)2527080-1 20726694 nnns volume:11 year:2019 number:2, p 151 https://doi.org/10.3390/cancers11020151 kostenfrei https://doaj.org/article/519c2b8ac25f4107a3c3dc723108577a kostenfrei https://www.mdpi.com/2072-6694/11/2/151 kostenfrei https://doaj.org/toc/2072-6694 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2019 2, p 151
allfieldsSound	10.3390/cancers11020151 doi (DE-627)DOAJ005964776 (DE-599)DOAJ519c2b8ac25f4107a3c3dc723108577a DE-627 ger DE-627 rakwb eng RC254-282 Laura Caleca verfasserin aut GFP-Fragment Reassembly Screens for the Functional Characterization of Variants of Uncertain Significance in Protein Interaction Domains of the <i<BRCA1</i< and <i<BRCA2</i< Genes 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Genetic testing for <i<BRCA1</i< and <i<BRCA2</i< genes has led to the identification of many unique variants of uncertain significance (VUS). Multifactorial likelihood models that predict the odds ratio for VUS in favor or against cancer causality, have been developed, but their use is conditioned by the amount of necessary data, which are difficult to obtain if a variant is rare. As an alternative, variants mapping to the coding regions can be examined using in vitro functional assays. BRCA1 and BRCA2 proteins promote genome protection by interacting with different proteins. In this study, we assessed the functional effect of two sets of variants in <i<BRCA</i< genes by exploiting the green fluorescent protein (GFP)-reassembly in vitro assay, which was set-up to test the BRCA1/BARD1, BRCA1/UbcH5a, and BRCA2/DSS1 interactions. Based on the findings observed for the validation panels of previously classified variants, BRCA1/UbcH5a and BRCA2/DSS1 binding assays showed 100% sensitivity and specificity in identifying pathogenic and non-pathogenic variants. While the actual efficiency of these assays in assessing the clinical significance of BRCA VUS has to be verified using larger validation panels, our results suggest that the GFP-reassembly assay is a robust method to identify variants affecting normal protein functioning and contributes to the classification of VUS. hereditary breast/ovarian cancer <i<BRCA1</i< <i<BRCA2</i< variant of uncertain significance functional assays protein-protein interaction Neoplasms. Tumors. Oncology. Including cancer and carcinogens Mara Colombo verfasserin aut Thomas van Overeem Hansen verfasserin aut Conxi Lázaro verfasserin aut Siranoush Manoukian verfasserin aut Michael T. Parsons verfasserin aut Amanda B. Spurdle verfasserin aut Paolo Radice verfasserin aut In Cancers MDPI AG, 2010 11(2019), 2, p 151 (DE-627)614095670 (DE-600)2527080-1 20726694 nnns volume:11 year:2019 number:2, p 151 https://doi.org/10.3390/cancers11020151 kostenfrei https://doaj.org/article/519c2b8ac25f4107a3c3dc723108577a kostenfrei https://www.mdpi.com/2072-6694/11/2/151 kostenfrei https://doaj.org/toc/2072-6694 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2019 2, p 151
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source	In Cancers 11(2019), 2, p 151 volume:11 year:2019 number:2, p 151
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authorswithroles_txt_mv	Laura Caleca @@aut@@ Mara Colombo @@aut@@ Thomas van Overeem Hansen @@aut@@ Conxi Lázaro @@aut@@ Siranoush Manoukian @@aut@@ Michael T. Parsons @@aut@@ Amanda B. Spurdle @@aut@@ Paolo Radice @@aut@@
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callnumber-first	R - Medicine
author	Laura Caleca
spellingShingle	Laura Caleca misc RC254-282 misc hereditary breast/ovarian cancer misc <i<BRCA1</i< misc <i<BRCA2</i< misc variant of uncertain significance misc functional assays misc protein-protein interaction misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens GFP-Fragment Reassembly Screens for the Functional Characterization of Variants of Uncertain Significance in Protein Interaction Domains of the <i<BRCA1</i< and <i<BRCA2</i< Genes
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topic_title	RC254-282 GFP-Fragment Reassembly Screens for the Functional Characterization of Variants of Uncertain Significance in Protein Interaction Domains of the <i<BRCA1</i< and <i<BRCA2</i< Genes hereditary breast/ovarian cancer <i<BRCA1</i< <i<BRCA2</i< variant of uncertain significance functional assays protein-protein interaction
topic	misc RC254-282 misc hereditary breast/ovarian cancer misc <i<BRCA1</i< misc <i<BRCA2</i< misc variant of uncertain significance misc functional assays misc protein-protein interaction misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
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title	GFP-Fragment Reassembly Screens for the Functional Characterization of Variants of Uncertain Significance in Protein Interaction Domains of the <i<BRCA1</i< and <i<BRCA2</i< Genes
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title_full	GFP-Fragment Reassembly Screens for the Functional Characterization of Variants of Uncertain Significance in Protein Interaction Domains of the <i<BRCA1</i< and <i<BRCA2</i< Genes
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author_browse	Laura Caleca Mara Colombo Thomas van Overeem Hansen Conxi Lázaro Siranoush Manoukian Michael T. Parsons Amanda B. Spurdle Paolo Radice
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title_sort	gfp-fragment reassembly screens for the functional characterization of variants of uncertain significance in protein interaction domains of the <i<brca1</i< and <i<brca2</i< genes
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title_auth	GFP-Fragment Reassembly Screens for the Functional Characterization of Variants of Uncertain Significance in Protein Interaction Domains of the <i<BRCA1</i< and <i<BRCA2</i< Genes
abstract	Genetic testing for <i<BRCA1</i< and <i<BRCA2</i< genes has led to the identification of many unique variants of uncertain significance (VUS). Multifactorial likelihood models that predict the odds ratio for VUS in favor or against cancer causality, have been developed, but their use is conditioned by the amount of necessary data, which are difficult to obtain if a variant is rare. As an alternative, variants mapping to the coding regions can be examined using in vitro functional assays. BRCA1 and BRCA2 proteins promote genome protection by interacting with different proteins. In this study, we assessed the functional effect of two sets of variants in <i<BRCA</i< genes by exploiting the green fluorescent protein (GFP)-reassembly in vitro assay, which was set-up to test the BRCA1/BARD1, BRCA1/UbcH5a, and BRCA2/DSS1 interactions. Based on the findings observed for the validation panels of previously classified variants, BRCA1/UbcH5a and BRCA2/DSS1 binding assays showed 100% sensitivity and specificity in identifying pathogenic and non-pathogenic variants. While the actual efficiency of these assays in assessing the clinical significance of BRCA VUS has to be verified using larger validation panels, our results suggest that the GFP-reassembly assay is a robust method to identify variants affecting normal protein functioning and contributes to the classification of VUS.
abstractGer	Genetic testing for <i<BRCA1</i< and <i<BRCA2</i< genes has led to the identification of many unique variants of uncertain significance (VUS). Multifactorial likelihood models that predict the odds ratio for VUS in favor or against cancer causality, have been developed, but their use is conditioned by the amount of necessary data, which are difficult to obtain if a variant is rare. As an alternative, variants mapping to the coding regions can be examined using in vitro functional assays. BRCA1 and BRCA2 proteins promote genome protection by interacting with different proteins. In this study, we assessed the functional effect of two sets of variants in <i<BRCA</i< genes by exploiting the green fluorescent protein (GFP)-reassembly in vitro assay, which was set-up to test the BRCA1/BARD1, BRCA1/UbcH5a, and BRCA2/DSS1 interactions. Based on the findings observed for the validation panels of previously classified variants, BRCA1/UbcH5a and BRCA2/DSS1 binding assays showed 100% sensitivity and specificity in identifying pathogenic and non-pathogenic variants. While the actual efficiency of these assays in assessing the clinical significance of BRCA VUS has to be verified using larger validation panels, our results suggest that the GFP-reassembly assay is a robust method to identify variants affecting normal protein functioning and contributes to the classification of VUS.
abstract_unstemmed	Genetic testing for <i<BRCA1</i< and <i<BRCA2</i< genes has led to the identification of many unique variants of uncertain significance (VUS). Multifactorial likelihood models that predict the odds ratio for VUS in favor or against cancer causality, have been developed, but their use is conditioned by the amount of necessary data, which are difficult to obtain if a variant is rare. As an alternative, variants mapping to the coding regions can be examined using in vitro functional assays. BRCA1 and BRCA2 proteins promote genome protection by interacting with different proteins. In this study, we assessed the functional effect of two sets of variants in <i<BRCA</i< genes by exploiting the green fluorescent protein (GFP)-reassembly in vitro assay, which was set-up to test the BRCA1/BARD1, BRCA1/UbcH5a, and BRCA2/DSS1 interactions. Based on the findings observed for the validation panels of previously classified variants, BRCA1/UbcH5a and BRCA2/DSS1 binding assays showed 100% sensitivity and specificity in identifying pathogenic and non-pathogenic variants. While the actual efficiency of these assays in assessing the clinical significance of BRCA VUS has to be verified using larger validation panels, our results suggest that the GFP-reassembly assay is a robust method to identify variants affecting normal protein functioning and contributes to the classification of VUS.
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title_short	GFP-Fragment Reassembly Screens for the Functional Characterization of Variants of Uncertain Significance in Protein Interaction Domains of the <i<BRCA1</i< and <i<BRCA2</i< Genes
url	https://doi.org/10.3390/cancers11020151 https://doaj.org/article/519c2b8ac25f4107a3c3dc723108577a https://www.mdpi.com/2072-6694/11/2/151 https://doaj.org/toc/2072-6694
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GFP-Fragment Reassembly Screens for the Functional Characterization of Variants of Uncertain Significance in Protein Interaction Domains of the <i<BRCA1</i< and <i<BRCA2</i< Genes

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