Reassessment of variants of uncertain significance in tumor suppressor genes using new ClinGen PP1/PP4 criteria guidance.

Abstract

Recently, new clinical genome resource (ClinGen) guidance focusing on cosegregation (PP1) and phenotype-specificity criteria (PP4) were introduced, based on the observation that the phenotype specificity could provide greater level of pathogenicity evidence. This study aimed to reassess variants of uncertain significance (VUS) found in tumor suppressor genes with specific phenotypes using these new recommendations. We retrieved VUS from an in-house database of all germline variants detected using sequencing since 2008. Patients carrying VUS from seven target tumor suppressor genes, NF1, TSC1, TSC2, RB1, PTCH1, STK11, and FH, were selected and the pathogenicity of each variant was reassessed using the new ClinGen PP1/PP4 criteria. In total, 128 unique VUS from 145 carriers were evaluated. Initial classification using the classic PP1/PP4 criteria from ACMG/AMP and point-based classification resulted in 21 variants being reclassified (2 pathogenic variants, 3 likely pathogenic variants [LPVs], 15 likely benign variants, and 1 benign variant), leaving 101 VUS. Applying the new ClinGen PP1/PP4 criteria, 32 (31.4%) remaining VUS were reclassified as LPVs. The reclassification rate was highest in STK11 (88.9%). Representative cases highlighted successful reclassification owing to highly specific phenotypes aligned with the new criteria. The new ClinGen PP1/PP4 criteria significantly improved the reclassification of VUS in tumor suppressor genes associated with specific phenotypes. The new criteria could substantially enhance the accuracy of variant classification.