Clinical Interpretation Challenges of Germline-Shared Somatic Variants in Cancer

Abstract

Abstract Objective To investigate the interpretation differences of germline-shared somatic variants. Methods A total of 123,302 COSMIC variants associated with hematologic malignant neoplasms were used. The pathogenicity and actionability of shared variants were analyzed based on the standardized guidelines. Results The overall frequency of variants shared in ClinVar/HGMD and COSMIC was 10%. The pathogenicity of 54 shared variants was pathogenic/likely pathogenic (P/LP; n = 30), variants of unknown significance (n = 3), and benign/likely benign (n = 21). In total, 30 P/LP variants were reclassified to tier I/tier II (83%) and tier III (17%) variants. Conclusions This is the first study about different clinical interpretations of shared variants based on the current standard guidelines. This study takes a meaningful step in bridging the interpretation gap between the somatic and germline variants.