Gene-specific criteria for PTEN variant curation: Recommendations from the ClinGen PTEN Expert Panel

• Type of Material: Article
• Authors: Jessica L Mester, GeneDx Inc; Rajarshi Ghosh, Baylor College of Medicine; Tina Pesaran, Ambry Genetics; Robert Huether, Tempus Labs; Rachid Karam, Ambry Genetics; Kathleen S. Hruska, GeneDx Inc; Helio A. Costa, Stanford University; Katherine Lachlan, University of Southampton; Joanne Ngeow, National Cancer Centre Singapore; Jill Barnholtz-Sloan, Case Comprehensive Cancer Centre; Kaitlin Sesock, Counsyl Inc; Felicia Hernandez, Ambry Genetics; Liying Zhang, Memorial Sloan Kettering Cancer Center; Laura Milko, University of North Carolina; Sharon E. Plon, Baylor College of Medicine; Madhuri Hegde, Emory University; Charis Eng, Case Comprehensive Cancer Centre
• Language: English
• Date: 2018-11-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Wiley Periodicals, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1002/humu.23636
• Title of Journal or Parent Work: Human Mutation
• ISSN: 1059-7794
• Volume: 39
• Issue: 11
• Start Page: 1581
• End Page: 1592
• Grant/Funding Information: The ClinGen Consortium is funded by the National Human Genome Research Institute of the National Institutes of Health through the following grants and contracts: U41HG006834 (Rehm), U41HG009649 (Bustamante/Plon), U01HG007436 (Bustamante/Plon), U01HG007437 (Berg), and U41HG009650 (Berg).
• Keywords: variant; Science & Technology; Genetics & Heredity; GENOTYPE-PHENOTYPE CORRELATIONS; CANCER-RISK; ClinGen; PTEN; LIPID PHOSPHATASE-ACTIVITY; criteria; FREQUENCY; classification; SUPPRESSOR; Life Sciences & Biomedicine; SUBCELLULAR-LOCALIZATION; COWDEN-SYNDROME; GERMLINE; MUTATIONS; HAMARTOMA TUMOR SYNDROME
• Research Categories: Engineering, Biomedical; Biology, Genetics; Chemistry, Biochemistry

Abstract

The ClinGen PTEN Expert Panel was organized by the ClinGen Hereditary Cancer Clinical Domain Working Group to assemble clinicians, researchers, and molecular diagnosticians with PTEN expertise to develop specifications to the 2015 ACMG/AMP Sequence Variant Interpretation Guidelines for PTEN variant interpretation. We describe finalized PTEN-specific variant classification criteria and outcomes from pilot testing of 42 variants with benign/likely benign (BEN/LBEN), pathogenic/likely pathogenic (PATH/LPATH), uncertain significance (VUS), and conflicting (CONF) ClinVar assertions. Utilizing these rules, classifications concordant with ClinVar assertions were achieved for 14/15 (93.3%) BEN/LBEN and 16/16 (100%) PATH/LPATH ClinVar consensus variants for an overall concordance of 96.8% (30/31). The variant where agreement was not reached was a synonymous variant near a splice donor with noncanonical sequence for which in silico models cannot predict the native site. Applying these rules to six VUS and five CONF variants, adding shared internal laboratory data enabled one VUS to be classified as LBEN and two CONF variants to be as classified as PATH and LPATH. This study highlights the benefit of gene-specific criteria and the value of sharing internal laboratory data for variant interpretation. Our PTEN-specific criteria and expertly reviewed assertions should prove helpful for laboratories and others curating PTEN variants.