Resolving Classification of PTEN Variants Using Gene-Specific ACMG/AMP Guidelines: A First Review of Curation Efforts by the ClinGen PTEN Variant Curation Expert Panel



2019 Clingen: Curating the Clinical Genome, Tempus-authored – The ClinGen PTEN Variant Curation Expert Panel (VCEP) provides assessment regarding the pathogenicity of germline PTEN variants with respect to a PTEN Hamartoma Tumor syndrome (MIM+601728) phenotype using PTEN-specific variant classification criteria based on the 2015 ACMG/AMP framework. Of highest priority are variants with conflicting ClinVar assertions (CONF) or those classified as variants of uncertain significance (VUS) by multiple submitters, with pathogenic (PATH), likely pathogenic (LPATH), benign (BEN), likely benign (LBEN), and other VUS also undergoing review. Since receiving full EP status, the PTEN VCEP has finalized classifications for 85 variants utilizing the Variant Curation Interface and uploaded assertions and detailed evidence summaries to ClinVar. We present a summary of the variants curated to date, highlighting PTEN VCEP resolution of variants with CONF or VUS assertions.

Classification resolution was achieved for 7/14 (50%) CONF variants, with 4 classified by the VCEP as BEN or LBEN and 3 as PATH or LPATH. Among 11 variants with VUS assertions by multiple submitters, the VCEP was able to reclassify 3 (27.3%), 1 as LBEN and 2 as LPATH. Shared internal laboratory data provided evidence critical for the resolution of 6 CONF variants and reclassification of 2 VUS. Most of the variants with ClinVar assertions of PATH/LPATH (42/44, 95.5%) or BEN/LBEN (14/16, 87.5%) retained that classification following VCEP review. The 19 variants currently classified as VUS by the VCEP include missense variants (n=7), variants in the promoter region or 3’ UTR (n=5), intronic or synonymous variants for which in silico tools are uninformative or conflicting (n=5), and in-frame indels (n=2). Notably, 7 of the 19 VUS (36.85%) are one benign supporting criterion away from a classification of LBEN.

All VUS and LPATH will undergo re-review two years from the last review date to seek new evidence that may aid in classification. Likewise, the PTEN VCEP plans to make updates to the current PTEN-specific variant classification criteria that may permit future resolution of variants currently classified as VUS. The presence of the PTEN VCEP’s assertions and evidence in ClinVar will enable laboratories and others performing PTEN variant analysis to consider aligning their own criteria and classifications with those of the VCEP, ultimately decreasing inter-laboratory classification discrepancies.

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Authors: Jessica L. Mester, Charis Eng, Madhuri Hedge, Helio Costa, Felicia Hernandez, Kathleen Hruska, Robert Huether, Rachid Karam, Katherine Lachlan, Joanne Ngeow, Melody Perpich, Tina Pesaran, Kaitlin Sesock, and Liying Zhang