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Diagnosing Hereditary Cancer Susceptibility Through Multigene Panel Testing

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Next Generation Sequencing Based Clinical Molecular Diagnosis of Human Genetic Disorders

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Abstract

Hereditary cancer diagnostics has considerably evolved with the clinical availability of multigene hereditary cancer panels. Over the past few years, multigene hereditary cancer panels have contributed to a growing number of diagnoses of hereditary cancer syndromes, including patients who would likely have been missed with a traditional testing approach. While panels are largely based on next generation sequencing (NGS), panel design is not always straightforward as there are a number of factors that need to be considered to correctly and reliably diagnose hereditary cancer syndromes. In this chapter, assay design and the interpretation/reporting of multigene panel results are reviewed from the perspective of a commercial genetic testing laboratory. Key observations in multigene panel cohorts are also presented, including the identification of atypical and expanding phenotypes, carriers of pathogenic variants in moderate penetrance genes, and individuals harboring pathogenic variants in multiple cancer susceptibility genes. Such observations have highlighted the need for data sharing and collaborative efforts, which is also discussed.

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Abbreviations

ACMG:

American College of Medical Genetics and Genomics

ASCO:

American Society of Clinical Oncology

CAP:

College of American Pathologists

ClinGen:

Clinical Genome Resource

CMMR-D:

Constitutional mismatch repair deficiency syndrome

CRC:

Colorectal cancer

ESP:

Exome Sequencing Project

ExAC:

Exome Aggregation Consortium

GTR:

Genetic Testing Registry

IARC:

International Agency for Research on Cancer

LOG:

Log of likelihood ratio

NCCN:

National Comprehensive Cancer Network

NGS:

Next generation sequencing

PGL-PCC:

Paraganglioma-pheochromocytoma

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  1. Department of Clinical Diagnostics, Ambry Genetics, Inc., 15 Argonaut, Aliso Viejo, CA, 92656, USA

    Holly LaDuca, Shuwei Li, A. J. Stuenkel, Virginia Speare, Jill S. Dolinsky & Elizabeth C. Chao

  2. Department of Pediatrics, Division of Genetics and Genomics, University of California, Irvine, Irvine, CA, USA

    Elizabeth C. Chao

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  1. Holly LaDuca
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    Lee-Jun C. Wong

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LaDuca, H., Li, S., Stuenkel, A.J., Speare, V., Dolinsky, J.S., Chao, E.C. (2017). Diagnosing Hereditary Cancer Susceptibility Through Multigene Panel Testing. In: Wong, LJ. (eds) Next Generation Sequencing Based Clinical Molecular Diagnosis of Human Genetic Disorders. Springer, Cham. https://doi.org/10.1007/978-3-319-56418-0_8

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