2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Leveraging extensive datasets to better classify <em>SMARCA4 </em>variants

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The document discusses the classification of variants in the SMARCA4 gene, which is associated with small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) and malignant and atypical/teratoid rhabdoid tumors (MRT/ATRT). These cancers are aggressive and have low long-term survival rates. The majority of SMARCA4 variants linked to these diseases are truncating variants, but some are missense variants, which makes classification challenging. Missense variants in SMARCA4 can also cause Coffin-Siris syndrome, leading to a high number of variants of uncertain significance (VUSs). The authors collected data on approximately 1500 SMARCA4 variants from multiple labs to better classify these missense variants. They made modifications to the American College of Medical Genetics and Genomics (ACMG) criteria to allow for the definitive classification of SMARCA4 variants. These modifications were based on other Variant Curation Expert Panels and the collected datasets. The authors were able to reclassify over 50 variants using the SMARCA4-specific modifications to the ACMG rules. This will help reduce the number of VUSs reported for SMARCA4. The authors aim to develop a ClinGen Variant Curation Expert Panel (VCEP) in the future. The methods used in this study included collecting data on the variants from multiple labs and making specifications to the ACMG criteria for SMARCA4. The document also includes a list of classified variants and the codes used for their classification.

Asset Subtitle

Presenting Author - Leora Witkowski, PhD, FACMG, FCCMG; Co-Author - Nadine Demko, MDCM, MSc; Co-Author - Elodie Petrecca, DEC; Co-Author - Marie Loncol, BSc; Co-Author - William D. Foulkes, MBBS, PhD;

Meta Tag

Cancer Syndromes

Genetic Testing

Co-Author Nadine Demko, MDCM, MSc

Co-Author Elodie Petrecca, DEC

Co-Author Marie Loncol, BSc

Co-Author William D. Foulkes, MBBS, PhD

Presenting Author Leora Witkowski, PhD, FACMG, FCCMG

Keywords

SMARCA4 gene

variants classification

small cell carcinoma

hypercalcemic type

rhabdoid tumors

truncating variants

missense variants

Coffin-Siris syndrome

variants of uncertain significance

ACMG criteria