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Empowering Clinicians to Resolve VUS: Presenting VUS Clarification Outcomes

Laboratory Genetics and Genomics
  • Primary Categories:
    • Laboratory Genetics
  • Secondary Categories:
    • Laboratory Genetics
Introduction:
Introduction:

Familial segregation studies provide essential, yet often underutilized, information for reclassifying Variants of Uncertain Significance (VUS). The VUS Clarification Service (VCS) program was designed to enhance the utility of familial segregation data. This unique approach offered a structured, three-tiered approach to assess potentially significant VUS and deliver customized guidance in clinical reports. In Tier 1, parental or offspring testing is performed to determine de novo status and phase without requiring a formal application or a formal application. If further segregation evidence is necessary, Tier 2 involves submitting a detailed application with comprehensive clinical and family information. For participants deemed ineligible for these services, Tier 3 includes a statement in the clinical report indicating ineligibility. This study evaluates the impact the VCS program on the reclassification of VUS, highlighting the role of our laboratory’s collaboration with participants and clinicians.  

Methods:
Methods:

A retrospective analysis of 231 cases eligible for the Blueprint Genetics VCS program was performed. A VUS is eligible for the program if it could potentially be reclassified to likely pathogenic with informative family member testing.  The Tier 2 cases that required an application, pedigree, and clinical and family information were reviewed. Each application was answered with an accepted or not accepted decision. If accepted, information that specified the necessary relatives for segregation analysis was provided. Variant interpretation was performed in accordance with modified American College of Medical Genetics and Genomics and Association for Molecular Pathology guidelines. 

Results:
Results:

The VCS program has shown significant clinical utility, with 83% (121/141) of eligible VUS cases successfully reclassified to likely pathogenic. Among the cases analyzed, 17% (20/141) remained classified as VUS. Missense variants comprised 65% (79/121) of reclassified variants. Most VUS cases were managed through Tier 1 at 82% (116/141), which did not require direct clinician contact or an application, which is particularly beneficial for busy clinics. Approximately 40% (90/231) of the 231 eligible cases were not accepted for various reasons, including the absence of negative controls, incomplete applications (clinical information, specimens, and informed consents), and discrepancies between family history and clinical presentation.  

Conclusion:
Conclusions:

This VCS program offering three service options to participants and health care providers, has proven valuable in aiding a clinical diagnosis. A significant proportion of eligible VUS were successfully reclassified as likely pathogenic. This program’s targeted VUS assessment pinpoint variants with a greater likelihood of reclassification, providing essential information to participants and clinicians during clinical reporting. This streamlined, tiered approach offers clinicians guidance in navigating the complexities of VUS interpretation, thereby addressing the clinical significance dilemma posed by VUS. Additionally, these results highlight the importance of familial segregation evidence and the critical collaboration between laboratories and clinicians to clarify the pathogenicity of VUS. This partnership enhances care of the participants by reducing the uncertainty associated with VUS.
 
 




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