Related Experiment Video
Updated: Jan 10, 2026
09:34
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
34.5K
Functional Analysis and Clinical Data Reclassify the DICER1 c.4206+1G>C Variant, Leading to Exon 22 Skipping, as
Sebastian Walpole1,2,3, Miren Itxaso Santiago-Vela4, Ulf Birkedal2,5
1School of Medicine, University of Queensland, Brisbane, Australia.
Clinical Genetics
|November 24, 2025
Summary
A DICER1 gene variant, initially unknown, was reclassified as likely pathogenic after functional analysis demonstrated it abrogates DICER1 function. This finding suggests updates to current genetic variant classification guidelines are needed.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Pathogenic germline variants in DICER1 are linked to various cancers, including pleuropulmonary blastoma and rhabdomyosarcomas.
- The DICER1 gene plays a crucial role in RNA interference and tumor suppression.
- Genetic variant classification relies on established guidelines like ACMG/AMP.
Purpose of the Study:
- To investigate a germline DICER1 variant (c.4206+1G>C) found in a patient with multiple tumors.
- To re-evaluate the pathogenicity of the DICER1 variant using functional analysis.
- To assess the adequacy of current ACMG/AMP guidelines for DICER1 variants.
Main Methods:
- Case report of a 35-year-old female with pineoblastoma, rhabdomyosarcoma, leiomyosarcoma, and meningiomas.
- Genetic sequencing to identify the DICER1 c.4206+1G>C variant.
- Functional assays to determine the impact of the variant on DICER1 function.
Main Results:
- The DICER1 c.4206+1G>C variant was initially classified as a variant of unknown significance (VUS).
- Functional analysis revealed the variant abrogates DICER1 function, supporting its reclassification.
- The variant was reclassified as likely pathogenic based on functional evidence.
Conclusions:
- The DICER1 c.4206+1G>C variant is likely pathogenic and contributes to the patient's tumor spectrum.
- Current ACMG/AMP gene-specific DICER1 guidelines may require modification regarding evidence strength for exon 22 skipping and the use of functional evidence (PS3).
- Accurate variant classification is critical for genetic counseling and patient management.
