When Germline Genetic Testing Results Are Unclear: Highlighting Variants of Uncertain Significance

Area of Science:

• Genetics
• Genomic Medicine
• Clinical Diagnostics

Background:

• High-throughput genetic testing, such as next-generation sequencing (NGS) and multigene panel testing, has increased the complexity of genetic analysis.
• Variants of uncertain significance (VUS) are common findings that pose significant interpretative challenges in clinical genetics.
• Misinterpretation of VUS can lead to adverse patient outcomes, including emotional distress and inappropriate medical interventions.

Purpose of the Study:

• To highlight the clinical challenges associated with interpreting variants of uncertain significance (VUS) in germline genetic testing.
• To illustrate how a lack of understanding of VUS by healthcare providers and patients can result in negative patient outcomes.
• To underscore the importance of accurate VUS interpretation in preventing unnecessary medical procedures and ensuring patient safety.

Main Methods:

• Review of current literature on genetic testing, NGS, and VUS interpretation.
• Analysis of a deidentified case study demonstrating the consequences of VUS misinterpretation.
• Discussion of the clinical implications and potential for patient harm.

Main Results:

• The case study revealed a negative patient outcome due to the misinterpretation of a germline VUS.
• Lack of understanding regarding VUS led to unnecessary surgical intervention for the patient.
• The findings underscore the critical need for improved genetic literacy among healthcare professionals and patients.

Conclusions:

• Accurate interpretation of variants of uncertain significance is crucial in clinical genetics to avoid patient harm.
• Enhanced education for healthcare providers and patients on VUS is necessary to improve genetic testing outcomes.
• Proper management of VUS findings can prevent unnecessary surgeries and reduce healthcare costs.