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Hum Mutat. 2018 Nov;39(11):1581-1592. doi: 10.1002/humu.23636.

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

Author information

1
GeneDx, Inc., Gaithersburg, Maryland.
2
Baylor College of Medicine, Houston, Texas.
3
Ambry Genetics, Aliso Viejo, California.
4
Tempus Labs, Chicago, Illinois.
5
Stanford University School of Medicine, Stanford, California.
6
Wessex Clinical Genetics Service, University Hospitals Southampton, Southampton, UK.
7
Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.
8
National Cancer Centre Singapore, Singapore.
9
Case Comprehensive Cancer Center, Cleveland, Ohio.
10
Case Western Reserve University School of Medicine, Cleveland, Ohio.
11
Counsyl, Inc., San Francisco, California.
12
Memorial Sloan Kettering Cancer Center, New York, New York.
13
University of North Carolina, Chapel Hill, North Carolina.
14
Emory University, Atlanta, Georgia.
15
PerkinElmer Genetics, Pittsburgh, Pennsylvania.
16
Cleveland Clinic Genomic Medicine Institute, Cleveland, Ohio.

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.

KEYWORDS:

ClinGen; PTEN; classification; criteria; variant

PMID:
30311380
DOI:
10.1002/humu.23636

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