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Variants of uncertain clinical significance in hereditary breast and ovarian cancer genes: best practices in functional analysis for clinical annotation

Variants of uncertain clinical significance in hereditary breast and ovarian cancer genes: best practices in functional analysis for clinical annotation
Variants of uncertain clinical significance in hereditary breast and ovarian cancer genes: best practices in functional analysis for clinical annotation
Germline DNA tests to identify pathogenic variants in genes linked to hereditary breast and ovarian cancer susceptibility have become widely available. However, the clinical utility of genetic testing depends on reliable evidence-based classification of sequence variants. Determination of pathogenicity traditionally relies on painstaking pedigree-based segregation analyses. However, the rapid increase in usage of germline DNA tests has led to the discovery of a large number of variants of uncertain clinical significance (VUS). For most VUS there is insufficient information for segregation analysis and therefore assessment of functional consequences is increasingly being used to support clinical annotation. Functional assays need to be accurate, robust, and reproducible to be used for clinical purposes. Here we use the lessons learned from BRCA1 and BRCA2 to identify best practices for the use of functional assays for clinical annotation of germline VUS in breast and ovarian cancer genes. We provide recommendations for the interpretation and use of established functional assays as well as for the development of new assays.
0022-2593
Monteiro, Alvaro
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Bouwman, Peter
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Nedergaard, Arne
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Eccles, Diana
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Millot, Gael A.
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Masson, Jean-Yves
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Schmidt, Marjanka K.
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Sharan, Shyam K.
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Scully, Ralph
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Wiesmuller, Lisa
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Couch, Fergus
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Vreeswijk, Maaike P.G.
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Monteiro, Alvaro
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Bouwman, Peter
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Nedergaard, Arne
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Eccles, Diana
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Millot, Gael A.
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Masson, Jean-Yves
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Schmidt, Marjanka K.
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Sharan, Shyam K.
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Scully, Ralph
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Wiesmuller, Lisa
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Couch, Fergus
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Vreeswijk, Maaike P.G.
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Monteiro, Alvaro, Bouwman, Peter, Nedergaard, Arne, Eccles, Diana, Millot, Gael A., Masson, Jean-Yves, Schmidt, Marjanka K., Sharan, Shyam K., Scully, Ralph, Wiesmuller, Lisa, Couch, Fergus and Vreeswijk, Maaike P.G. (2019) Variants of uncertain clinical significance in hereditary breast and ovarian cancer genes: best practices in functional analysis for clinical annotation. Journal of Medical Genetics. (In Press)

Record type: Article

Abstract

Germline DNA tests to identify pathogenic variants in genes linked to hereditary breast and ovarian cancer susceptibility have become widely available. However, the clinical utility of genetic testing depends on reliable evidence-based classification of sequence variants. Determination of pathogenicity traditionally relies on painstaking pedigree-based segregation analyses. However, the rapid increase in usage of germline DNA tests has led to the discovery of a large number of variants of uncertain clinical significance (VUS). For most VUS there is insufficient information for segregation analysis and therefore assessment of functional consequences is increasingly being used to support clinical annotation. Functional assays need to be accurate, robust, and reproducible to be used for clinical purposes. Here we use the lessons learned from BRCA1 and BRCA2 to identify best practices for the use of functional assays for clinical annotation of germline VUS in breast and ovarian cancer genes. We provide recommendations for the interpretation and use of established functional assays as well as for the development of new assays.

Text
Functional framework for HBOC genes JMG REV OCT 2019_track - Accepted Manuscript
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Accepted/In Press date: 1 December 2019

Identifiers

Local EPrints ID: 436745
URI: http://eprints.soton.ac.uk/id/eprint/436745
ISSN: 0022-2593
PURE UUID: f073be35-5cf9-4ddb-acbc-ed749e8182e4
ORCID for Diana Eccles: ORCID iD orcid.org/0000-0002-9935-3169

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Date deposited: 03 Jan 2020 17:30
Last modified: 22 Nov 2021 07:55

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Contributors

Author: Alvaro Monteiro
Author: Peter Bouwman
Author: Arne Nedergaard
Author: Diana Eccles ORCID iD
Author: Gael A. Millot
Author: Jean-Yves Masson
Author: Marjanka K. Schmidt
Author: Shyam K. Sharan
Author: Ralph Scully
Author: Lisa Wiesmuller
Author: Fergus Couch
Author: Maaike P.G. Vreeswijk

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