The Impact of Gene-Specific Guidelines on Variant Reassessment: Perspectives from a Hereditary Cancer Clinic
Laboratory Genetics and Genomics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction:
Variant reassessments are essential touchpoints by which new evidence is translated to patient care. However, reassessments present a significant bottleneck for clinical laboratories facing tight turnaround times and limited resources. In recent years, gene-specific guidelines, or criteria specifications (CSpecs), developed by ClinGen expert panels have emerged as a resource to facilitate more accurate, standardized interpretation. Supplemental to ACMG guidelines, CSpecs contain recommendations for the modification or applicability of evidence criteria on the basis of gene-specific disease mechanisms. Large-scale application of CSpecs to variant databases has demonstrated their ability to reduce variants of uncertain significance (VUS) and resolve conflicting interpretations, findings which have been extrapolated to potentially alleviate the burden of reassessment. This study describes the experiences of a single hereditary cancer clinic with CSpec integration and their contribution to reassessment outcomes in clinical practice.
Methods:
This study reviewed variant reassessments conducted at Mount Sinai Hospital, Toronto between August 2023 and October 2024. Reassessments are initiated every 2 years after initial analysis, excluding variants in terminal classifications (B/P), or upon request by physicians and external laboratories. This review was restricted to variants in genes with CSpecs released within the past year, where the last assessment would have occurred prior to CSpec integration, and for which there was sufficient data: BRCA1, BRCA2, APC, and ATM. Variants are classified as Benign (B), Likely Benign (LB), Uncertain Significance, Likely Pathogenic (LP), or Pathogenic (P) per ACMG standards.
Results:
Sixty-one BRCA1 variants underwent reassessment and 64% (n=39) were reclassified, all constituting downgrades to clinically meaningful classifications: 37 VUS to LB/B, and 2 LB to B. Of the 118 BRCA2 variants reassessed, 68% (n=80) were reclassified: 47 VUS to LB/B, 30 LB to B, and 3 LP upgraded to P classifications. Notably, 67% (n=41/61) of total VUS to LB reclassifications in BRCA1 and BRCA2 were informed by the sole application of the modified BP1_Strong standalone criterion.
Twenty-four APC variants were reassessed and 54% (n=13) were reclassified: 6 VUS were downgraded to LB, 3 LB variants to B, and 2 VUS were upgraded to LP classifications. Additionally, 2 APC variants were downgraded from P to VUS: a start-loss and an exon 1-2 deletion, which no longer qualify for PVS1 per the CSpec decision tree.
Of the 44 ATM variants reassessed, 14% (n=6) were reclassified. Four VUS were downgraded to LB. Two ATM variants were reclassified to VUS from likely benign/pathogenic classifications as evidence used in previous assessments no longer applied per the updated guidelines.
In total, 247 variant reassessments were included in this study, of which 56% (n=138) were reclassified. Additionally, 66% (n=80/121) of VUS were resolved and predominantly downgraded to a LB/B classification (n=78; 98%), while 25% (n=61) of reassessment events resulted in terminal classifications.
Conclusion:
The use of CSpecs streamlines assessment by filtering out non-applicable evidence, specifying parameters for vaguely or inconsistently applied criteria, and through the curation of evidence repositories and other resources. For example, CSpecs consistently feature points-based systems for clinical evidence (phenotypic, co-occurrence, and co-segregation data) and calibrated population frequency thresholds, facilitating standardized application of these criteria.
These findings demonstrate a meaningful increase in clinical utility following CSpec integration, enabling clearer pathways for patient care and efficient prioritization of variants for reassessment. Instances where a variant was reclassified as a VUS from a LP/P classification highlight the importance of gene-specific considerations for accurate interpretation. Variants downgraded with only a single criterion will be re-evaluated to determine if these downgrades were premature or if new evidence corroborates these reclassifications.
Variant reassessments are essential touchpoints by which new evidence is translated to patient care. However, reassessments present a significant bottleneck for clinical laboratories facing tight turnaround times and limited resources. In recent years, gene-specific guidelines, or criteria specifications (CSpecs), developed by ClinGen expert panels have emerged as a resource to facilitate more accurate, standardized interpretation. Supplemental to ACMG guidelines, CSpecs contain recommendations for the modification or applicability of evidence criteria on the basis of gene-specific disease mechanisms. Large-scale application of CSpecs to variant databases has demonstrated their ability to reduce variants of uncertain significance (VUS) and resolve conflicting interpretations, findings which have been extrapolated to potentially alleviate the burden of reassessment. This study describes the experiences of a single hereditary cancer clinic with CSpec integration and their contribution to reassessment outcomes in clinical practice.
Methods:
This study reviewed variant reassessments conducted at Mount Sinai Hospital, Toronto between August 2023 and October 2024. Reassessments are initiated every 2 years after initial analysis, excluding variants in terminal classifications (B/P), or upon request by physicians and external laboratories. This review was restricted to variants in genes with CSpecs released within the past year, where the last assessment would have occurred prior to CSpec integration, and for which there was sufficient data: BRCA1, BRCA2, APC, and ATM. Variants are classified as Benign (B), Likely Benign (LB), Uncertain Significance, Likely Pathogenic (LP), or Pathogenic (P) per ACMG standards.
Results:
Sixty-one BRCA1 variants underwent reassessment and 64% (n=39) were reclassified, all constituting downgrades to clinically meaningful classifications: 37 VUS to LB/B, and 2 LB to B. Of the 118 BRCA2 variants reassessed, 68% (n=80) were reclassified: 47 VUS to LB/B, 30 LB to B, and 3 LP upgraded to P classifications. Notably, 67% (n=41/61) of total VUS to LB reclassifications in BRCA1 and BRCA2 were informed by the sole application of the modified BP1_Strong standalone criterion.
Twenty-four APC variants were reassessed and 54% (n=13) were reclassified: 6 VUS were downgraded to LB, 3 LB variants to B, and 2 VUS were upgraded to LP classifications. Additionally, 2 APC variants were downgraded from P to VUS: a start-loss and an exon 1-2 deletion, which no longer qualify for PVS1 per the CSpec decision tree.
Of the 44 ATM variants reassessed, 14% (n=6) were reclassified. Four VUS were downgraded to LB. Two ATM variants were reclassified to VUS from likely benign/pathogenic classifications as evidence used in previous assessments no longer applied per the updated guidelines.
In total, 247 variant reassessments were included in this study, of which 56% (n=138) were reclassified. Additionally, 66% (n=80/121) of VUS were resolved and predominantly downgraded to a LB/B classification (n=78; 98%), while 25% (n=61) of reassessment events resulted in terminal classifications.
Conclusion:
The use of CSpecs streamlines assessment by filtering out non-applicable evidence, specifying parameters for vaguely or inconsistently applied criteria, and through the curation of evidence repositories and other resources. For example, CSpecs consistently feature points-based systems for clinical evidence (phenotypic, co-occurrence, and co-segregation data) and calibrated population frequency thresholds, facilitating standardized application of these criteria.
These findings demonstrate a meaningful increase in clinical utility following CSpec integration, enabling clearer pathways for patient care and efficient prioritization of variants for reassessment. Instances where a variant was reclassified as a VUS from a LP/P classification highlight the importance of gene-specific considerations for accurate interpretation. Variants downgraded with only a single criterion will be re-evaluated to determine if these downgrades were premature or if new evidence corroborates these reclassifications.
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