BRCA ‘variants of unknown significance’ need regular review to facilitate optimal patient management
Association of Breast Surgery ePoster Library. Irwin G. 05/15/17; 166343; P050
Mr. Gareth Irwin
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Abstract
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Introduction
Most BRCA1 and 2 mutations are known to either be pathogenic or benign but for some their clinical significance is unknown, leading to uncertainty regarding management. Periodically, these 'variants of unknown significance' are reclassified by ClinVar, IARC or Align-GVGD, gene classification databases, potentially leading to a change in optimal management.
Methods
All VUS of BRCA1 and 2 were identified from the Northern Ireland BRCA database and reanalysed by updated review of ClinVar, IARC, BRCA1 Circos or Align-GVGD to evaluate whether or not they had been reclassified, and if this reclassification may have an impact on clinical management.
Results
170 VUS were identified: 67 in BRCA1 and 103 in BRCA2. Of these 4 BRCA1 and 5 BRCA2 VUS were reclassified as either definitely or probably pathogenic. 78% of BRCA1 and 71% of BRCA2 VUSs were reclassified as either benign, probably benign or of little impact. 21% of all the VUSs remained unable to be classified.
Conclusions
As more information is gleaned about VUS the frequency of their reclassification is increasing. This study highlights the need to revisit VUSs as their reclassification may have clinical implications, with 5% of patients in this study now being diagnosed as either definitely or probably pathogenic. In addition, up to 78% could be reassured by an unknown variant being reclassified as benign. This has implications for consent to undertake genetic testing and the need to update patients as more information becomes available.
Most BRCA1 and 2 mutations are known to either be pathogenic or benign but for some their clinical significance is unknown, leading to uncertainty regarding management. Periodically, these 'variants of unknown significance' are reclassified by ClinVar, IARC or Align-GVGD, gene classification databases, potentially leading to a change in optimal management.
Methods
All VUS of BRCA1 and 2 were identified from the Northern Ireland BRCA database and reanalysed by updated review of ClinVar, IARC, BRCA1 Circos or Align-GVGD to evaluate whether or not they had been reclassified, and if this reclassification may have an impact on clinical management.
Results
170 VUS were identified: 67 in BRCA1 and 103 in BRCA2. Of these 4 BRCA1 and 5 BRCA2 VUS were reclassified as either definitely or probably pathogenic. 78% of BRCA1 and 71% of BRCA2 VUSs were reclassified as either benign, probably benign or of little impact. 21% of all the VUSs remained unable to be classified.
Conclusions
As more information is gleaned about VUS the frequency of their reclassification is increasing. This study highlights the need to revisit VUSs as their reclassification may have clinical implications, with 5% of patients in this study now being diagnosed as either definitely or probably pathogenic. In addition, up to 78% could be reassured by an unknown variant being reclassified as benign. This has implications for consent to undertake genetic testing and the need to update patients as more information becomes available.
Introduction
Most BRCA1 and 2 mutations are known to either be pathogenic or benign but for some their clinical significance is unknown, leading to uncertainty regarding management. Periodically, these 'variants of unknown significance' are reclassified by ClinVar, IARC or Align-GVGD, gene classification databases, potentially leading to a change in optimal management.
Methods
All VUS of BRCA1 and 2 were identified from the Northern Ireland BRCA database and reanalysed by updated review of ClinVar, IARC, BRCA1 Circos or Align-GVGD to evaluate whether or not they had been reclassified, and if this reclassification may have an impact on clinical management.
Results
170 VUS were identified: 67 in BRCA1 and 103 in BRCA2. Of these 4 BRCA1 and 5 BRCA2 VUS were reclassified as either definitely or probably pathogenic. 78% of BRCA1 and 71% of BRCA2 VUSs were reclassified as either benign, probably benign or of little impact. 21% of all the VUSs remained unable to be classified.
Conclusions
As more information is gleaned about VUS the frequency of their reclassification is increasing. This study highlights the need to revisit VUSs as their reclassification may have clinical implications, with 5% of patients in this study now being diagnosed as either definitely or probably pathogenic. In addition, up to 78% could be reassured by an unknown variant being reclassified as benign. This has implications for consent to undertake genetic testing and the need to update patients as more information becomes available.
Most BRCA1 and 2 mutations are known to either be pathogenic or benign but for some their clinical significance is unknown, leading to uncertainty regarding management. Periodically, these 'variants of unknown significance' are reclassified by ClinVar, IARC or Align-GVGD, gene classification databases, potentially leading to a change in optimal management.
Methods
All VUS of BRCA1 and 2 were identified from the Northern Ireland BRCA database and reanalysed by updated review of ClinVar, IARC, BRCA1 Circos or Align-GVGD to evaluate whether or not they had been reclassified, and if this reclassification may have an impact on clinical management.
Results
170 VUS were identified: 67 in BRCA1 and 103 in BRCA2. Of these 4 BRCA1 and 5 BRCA2 VUS were reclassified as either definitely or probably pathogenic. 78% of BRCA1 and 71% of BRCA2 VUSs were reclassified as either benign, probably benign or of little impact. 21% of all the VUSs remained unable to be classified.
Conclusions
As more information is gleaned about VUS the frequency of their reclassification is increasing. This study highlights the need to revisit VUSs as their reclassification may have clinical implications, with 5% of patients in this study now being diagnosed as either definitely or probably pathogenic. In addition, up to 78% could be reassured by an unknown variant being reclassified as benign. This has implications for consent to undertake genetic testing and the need to update patients as more information becomes available.
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