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

https://doi.org/10.1016/j.jmoldx.2023.03.012Get rights and content

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.

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Supported exclusively by the Association for Molecular Pathology.

Disclosures: To provide active management of potential perceived and/or actual conflicts of interest (COIs), a Working Group chair without relevant conflicts was appointed, and COI disclosures were requested from and/or provided by all authors throughout all phases of the consensus manuscript development process. K.D.F.H. is employed by Ambry Genetics (Aliso Viejo, CA). S.E.L. is employed by Invitae (Bethesda, MD). A.S. is employed by Veritas Genetics (Danvers, MA), a subsidiary of LetsGetChecked (PrivaPath Diagnostics, Dublin, Ireland); is cofounder of Opus Genomics (Durham, NC); and is equity holder in Opus Genomics, LetsGetChecked, and PathFinder Health (Seattle, WA).

The Next Generation Sequencing Germline Variant Confirmation Working Group of the Clinical Practice Committee, Association for Molecular Pathology (AMP), with organizational representation from the National Society of Genetic Counselors (K.D.F.H.). The AMP 2021 Clinical Practice Committee consisted of Jane Gibson (Chair), Fatimah Nahhas, Steven Sperber, Rashmi Goswami, Michael Kluk, Susan Hsiao, David Eberhard, Joseph Yao, Blake Buchan, Joshua Coleman, Elaine Gee, Andres Madrigal, and Jack Tung.

This article does not define standard of practice, and there may be alternatives. See Disclaimers for further details.

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