The rapid development of genomic sequencing technologies has decreased the cost of genetic analysis to the extent that it seems plausible that genome-scale sequencing could have widespread availability in pediatric care. Genomic sequencing provides a powerful diagnostic modality for patients who manifest symptoms of monogenic disease and an opportunity to detect health conditions before their development. However, many technical, clinical, ethical, and societal challenges should be addressed before such technology is widely deployed in pediatric practice. This article provides an overview of the Newborn Sequencing in Genomic Medicine and Public Health Consortium, which is investigating the application of genome-scale sequencing in newborns for both diagnosis and screening.
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 non-canonical 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.
Genome-scale sequencing creates vast amounts of genomic data, increasing
the challenge of clinical sequence variant interpretation. The demand for
high-quality interpretation requires multiple specialties to join forces to
accelerate the interpretation of sequence variant pathogenicity. With over 600
international members including clinicians, researchers, and laboratory
diagnosticians, the Clinical Genome Resource (ClinGen), funded by the National
Institutes of Health (NIH), is forming expert groups to systematically evaluate
variants in clinically relevant genes. Here, we describe the first ClinGen
Variant Curation Expert Panels (VCEPs), development of consistent and
streamlined processes for establishing new VCEPs, and creation of standard
operating procedures (SOPs) for VCEPs to define application of the ACMG/AMP
guidelines for sequence variant interpretation in specific genes or diseases.
Additionally, ClinGen has created user interfaces to enhance reliability of
curation and a Sequence Variant Interpretation Working Group (SVI WG) to
harmonize guideline specifications and ensure consistency between groups. The
expansion of VCEPs represents the primary mechanism by which curation of a
substantial fraction of genomic variants can be accelerated and ultimately
undertaken systematically and comprehensively. We welcome groups to utilize our
resources and become involved in our effort to create a publicly accessible,
centralized resource for clinically relevant genes and variants.
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