Genomic Screening Test Details
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Background
Genomic Screening tests provide genomic information for individuals over 18 years of age who are interested in learning more about their health, reproductive and/or pharmacogenomic risks. This test provides high quality genome sequencing, as well as unparalleled data interpretation. Results will be returned to the ordering physician in a concise report.
There are two testing options.
- The first option is the Genomic Screening Test, which is limited to findings in 59 medically actionable genes, with the option to include pharmacogenomic (PGx) results.
- The second option is the Expanded Genomic Screening Test, which analyzes >3,500 genes with strong or definitive disease association and includes interpretations on pathogenic and likely pathogenic variants, carrier status variants, risk alleles and PGx results.
Complete genomic data for either test option is available in BAM or VCF files.
Genomic Screening Consultation
If you would like assistance in determining the appropriateness of genomic screening for you or your patient, you may contact us by phone or submit pages 2–3 of our requisition form, along with your contact information, and we will contact you.
Indication for Testing
These tests are intended as screening for healthy adults over 18 years of age who are interested in learning more about their genomic variants and implications that information may have on health and reproductive risks. These tests are not intended to be utilized for diagnostic purposes and will not include patient-specific analysis for specific diseases or conditions. We offer diagnostic genome and exome services for that purpose.
Methodology
Genome sequencing and variant interpretation: Genome sequence is generated from genomic DNA that is fragmented and barcoded followed by sequencing on the Illumina NoveSeq instrument with a minimum coverage of at least 20X for 95% of the genome. Technical sensitivity of this assay is 99.84% (95% CI: 99.83-99.85%) and positive predictive value is 99.18% (95% CI: 99.12-99.24%). Reads are aligned to the NCBI reference sequence (GRCh37), using the Burrows-Wheeler Aligner (BWA), and variant calls are made using the Genomic Analysis Tool Kit (GATK).
Read More...Variants are subsequently limited to either 1) 59 medically actionable for the Genomic Screening Test or 2) >3,500 genes with a strong or definitive level of published evidence for a gene-disease association for the Expanded Genomic Screening Test. The remaining variants are subsequently filtered to identify: (1) variants previously classified by our laboratory as pathogenic or likely pathogenic; (2) variants classified as disease causing mutations in public databases that have a minor allele frequency <5.0% in the Genome Aggregation Database (gnomAD, http://gnomadexac.broadinstitute.org/); (3) nonsense, frameshift, and +/-1,2 splice-site variants in disease-associated genes with a minor allele frequency ≤1.0% in gnomAD; and (4) curated established and likely risk alleles with an odds-ratio of at least 2-4. The evidence for disease-causality is then evaluated for each variant identified from the filtering strategies listed above and variants are classified based on ACMG/AMP criteria (Richards et al. 2015) with ClinGen rule specifications (https://www.clinicalgenome.org/working-groups/sequence-variant-interpretation/), or our internal framework for classification of risk alleles (https://www.biorxiv.org/content/10.1101/556316v1). Variants are reported according to HGVS nomenclature (http://varnomen.hgvs.org/). Only those variants with evidence for causing or contributing to disease are reported. All disease-associated variants on this report are confirmed via Sanger sequencing or another orthogonal technology. Please contact the laboratory for additional information.
PGx: Genotype calls for specific genomic positions are identified using the Genomic Analysis Tool Kit (GATK) and a custom script. Diplotype and phenotype are generated using the Clinical Pharmacogenetics Implementation Consortium (CPIC®) and PharmGKB guidelines. The following pharmacogenomic variants are detected by this assay (details here). This test does not report all pharmacogenomic variants that might alter protein function. Therefore, a result does not exclude the possibility that an individual has a different phenotype that may alter drug response. This risk may vary among ethnic groups. This assay cannot determine if multiple variants in the same gene are present in cis or trans, leading to an inability to definitively assign a diplotype and phenotype. This test does not detect copy number variants.
LessLimitations
Specific types of genetic variation, such as triplet repeat expansions, structural variation, regions with high homology, and copy number events are currently not reliably detected by genome sequencing. Additionally, while genome sequencing adequately covers ~95% of the genome; there are certain regions for which the assay may fail to sufficiently generate sequence information. Moreover, not all disease-associated genes have been identified and the clinical significance of variation in many genes is not well understood. Variant interpretation may change over time if more information becomes available. Gene-level coverage information for both tests is available online and details regarding the coverage of genes associated with a specific indication can be determined upon request. For additional questions, you also may visit our Frequently Asked Questions page.
Genome Sequencing
Genome Sequencing offers a unbiased look at patients’ genetic makeup that can provide them with information about the diseases they have, as well as risks for other diseases.
Interested in Exome or Genome Sequencing
For further information, please contact the
Laboratory for Molecular Medicine
Phone: 617-768-8500
Fax: (617) 768-8513
Email: lmm@partners.org
Amy Hernandez, MS, CGC
Director of Genetic Counseling
Phone: (617) 768-8516
Email: alhernandez@partners.org
