Specifications of the ACMG/AMP Variant Classification Guidelines for Germline DICER1 Variant Curation

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Germline pathogenic variants in DICER1 are linked to various tumors.
• Accurate DICER1 variant classification is crucial for diagnosing tumor predisposition and guiding surveillance.
• Existing general guidelines (ACMG/AMP) lack gene-specific details for DICER1, leading to subjectivity.

Purpose of the Study:

• To develop and pilot gene-specific ACMG/AMP guidelines for DICER1 germline variant curation.
• To improve the accuracy and consistency of DICER1 variant classification.
• To reduce the frequency of uncertain variant classifications.

Main Methods:

• Formation of the DICER1 and miRNA-Processing Genes Variant Curation Expert Panel (VCEP) under ClinGen.
• Adaptation and piloting of guidelines using the FDA-approved ClinGen protocol.
• Classification of 40 diverse DICER1 variants (14 P/LP, 12 B/LB, 14 VUS/conflicting).

Main Results:

• Clinically meaningful classifications achieved for 82.5% (33/40) of pilot variants.
• 100% concordance for known Pathogenic/Likely Pathogenic and Benign/Likely Benign variants.
• Half of uncertain/conflicting variants were resolved (7/14), with 4 classified as LB and 3 as LP.

Conclusions:

• DICER1-specific guidelines effectively classify known variants and reduce uncertain classifications.
• The developed framework enhances objectivity and consistency in DICER1 variant curation.
• Adoption of these guidelines is recommended for improved diagnostic reliability and patient care.