Recommendations for Next-Generation Sequencing Germline Variant Confirmation: A Joint Report of the Association for Molecular Pathology and National Society of Genetic Counselors

Kristy R Crooks; Kelly D Farwell Hagman; Diana Mandelker; Avni Santani; Ryan J Schmidt; Robyn L Temple-Smolkin; Stephen E Lincoln

doi:10.1016/j.jmoldx.2023.03.012

Recommendations for Next-Generation Sequencing Germline Variant Confirmation: A Joint Report of the Association for Molecular Pathology and National Society of Genetic Counselors

J Mol Diagn. 2023 Jul;25(7):411-427. doi: 10.1016/j.jmoldx.2023.03.012. Epub 2023 May 17.

Authors

Kristy R Crooks¹, Kelly D Farwell Hagman², Diana Mandelker³, Avni Santani⁴, Ryan J Schmidt⁵, Robyn L Temple-Smolkin⁶, Stephen E Lincoln⁷

Affiliations

¹ NGS Germline Variant Confirmation Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Electronic address: [email protected].
² NGS Germline Variant Confirmation Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Clinical Diagnostics, Ambry Genetics, Aliso Viejo, California.
³ NGS Germline Variant Confirmation Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
⁴ NGS Germline Variant Confirmation Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; LetsGetChecked, PrivaPath Diagnostics, Dublin, Ireland; Veritas Genetics, Danvers, Massachusetts.
⁵ NGS Germline Variant Confirmation Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California; Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California.
⁶ Association for Molecular Pathology, Rockville, Maryland.
⁷ NGS Germline Variant Confirmation Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; InVitae, Bethesda, Maryland.

PMID: 37207865
DOI: 10.1016/j.jmoldx.2023.03.012

Abstract

Clinical laboratory implementation of next-generation sequencing (NGS)-based constitutional genetic testing has been rapid and widespread. In the absence of widely adopted comprehensive guidance, there remains substantial variability among laboratories in the practice of NGS. One issue of sustained discussion in the field is whether and to what extent orthogonal confirmation of genetic variants identified by NGS is necessary or helpful. The Association for Molecular Pathology Clinical Practice Committee convened the NGS Germline Variant Confirmation Working Group to assess current evidence regarding orthogonal confirmation and to establish recommendations for standardizing orthogonal confirmation practices to support quality patient care. On the basis of the results of a survey of the literature, a survey of laboratory practices, and subject expert matter consensus, eight recommendations are presented, providing a common framework for clinical laboratory professionals to develop or refine individualized laboratory policies and procedures regarding orthogonal confirmation of germline variants detected by NGS.

Publication types

Review

MeSH terms

Counselors*
Genetic Testing / methods
Germ Cells
High-Throughput Nucleotide Sequencing / methods
Humans
Pathology, Molecular*