Combining evidence for and against pathogenicity for variants in cancer susceptibility genes: CanVIG-UK consensus recommendations
Combining evidence for and against pathogenicity for variants in cancer susceptibility genes: CanVIG-UK consensus recommendations
Accurate classification of variants in cancer susceptibility genes (CSGs) is key for correct estimation of cancer risk and management of patients. Consistency in the weighting assigned to individual elements of evidence has been much improved by the American College of Medical Genetics (ACMG) 2015 framework for variant classification, UK Association for Clinical Genomic Science (UK-ACGS) Best Practice Guidelines and subsequent Cancer Variant Interpretation Group UK (CanVIG-UK) consensus specification for CSGs. However, considerable inconsistency persists regarding practice in the combination of evidence elements. CanVIG-UK is a national subspecialist multidisciplinary network for cancer susceptibility genomic variant interpretation, comprising clinical scientist and clinical geneticist representation from each of the 25 diagnostic laboratories/clinical genetic units across the UK and Republic of Ireland. Here, we summarise the aggregated evidence elements and combinations possible within different variant classification schemata currently employed for CSGs (ACMG, UK-ACGS, CanVIG-UK and ClinGen gene-specific guidance for PTEN, TP53 and CDH1). We present consensus recommendations from CanVIG-UK regarding (1) consistent scoring for combinations of evidence elements using a validated numerical 'exponent score' (2) new combinations of evidence elements constituting likely pathogenic' and 'pathogenic' classification categories, (3) which evidence elements can and cannot be used in combination for specific variant types and (4) classification of variants for which there are evidence elements for both pathogenicity and benignity.
genetic testing, genetic variation, genetics, genomics, medical
Garrett, Alice
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Durkie, Miranda
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Callaway, Alison
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Burghel, George J.
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Robinson, Rachel
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Drummond, James
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Torr, Bethany
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Cubuk, Cankut
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Berry, Ian R.
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Wallace, Andrew J.
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Ellard, Sian
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Eccles, Diana M.
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Tischkowitz, Marc
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Hanson, Helen
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Turnbull, Clare
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Garrett, Alice
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Durkie, Miranda
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Callaway, Alison
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Burghel, George J.
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Robinson, Rachel
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Drummond, James
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Torr, Bethany
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Cubuk, Cankut
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Berry, Ian R.
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Wallace, Andrew J.
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Ellard, Sian
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Eccles, Diana M.
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Tischkowitz, Marc
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Hanson, Helen
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Turnbull, Clare
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Garrett, Alice, Durkie, Miranda, Callaway, Alison, Burghel, George J., Robinson, Rachel, Drummond, James, Torr, Bethany, Cubuk, Cankut, Berry, Ian R., Wallace, Andrew J., Ellard, Sian, Eccles, Diana M., Tischkowitz, Marc, Hanson, Helen and Turnbull, Clare
(2020)
Combining evidence for and against pathogenicity for variants in cancer susceptibility genes: CanVIG-UK consensus recommendations.
Journal of Medical Genetics, [107248].
(doi:10.1136/jmedgenet-2020-107248).
Abstract
Accurate classification of variants in cancer susceptibility genes (CSGs) is key for correct estimation of cancer risk and management of patients. Consistency in the weighting assigned to individual elements of evidence has been much improved by the American College of Medical Genetics (ACMG) 2015 framework for variant classification, UK Association for Clinical Genomic Science (UK-ACGS) Best Practice Guidelines and subsequent Cancer Variant Interpretation Group UK (CanVIG-UK) consensus specification for CSGs. However, considerable inconsistency persists regarding practice in the combination of evidence elements. CanVIG-UK is a national subspecialist multidisciplinary network for cancer susceptibility genomic variant interpretation, comprising clinical scientist and clinical geneticist representation from each of the 25 diagnostic laboratories/clinical genetic units across the UK and Republic of Ireland. Here, we summarise the aggregated evidence elements and combinations possible within different variant classification schemata currently employed for CSGs (ACMG, UK-ACGS, CanVIG-UK and ClinGen gene-specific guidance for PTEN, TP53 and CDH1). We present consensus recommendations from CanVIG-UK regarding (1) consistent scoring for combinations of evidence elements using a validated numerical 'exponent score' (2) new combinations of evidence elements constituting likely pathogenic' and 'pathogenic' classification categories, (3) which evidence elements can and cannot be used in combination for specific variant types and (4) classification of variants for which there are evidence elements for both pathogenicity and benignity.
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Accepted/In Press date: 13 August 2020
e-pub ahead of print date: 18 November 2020
Additional Information:
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.
Keywords:
genetic testing, genetic variation, genetics, genomics, medical
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Local EPrints ID: 452134
URI: http://eprints.soton.ac.uk/id/eprint/452134
ISSN: 0022-2593
PURE UUID: a599985a-0375-4d32-b50d-3c0afbbac233
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Date deposited: 25 Nov 2021 17:55
Last modified: 17 Mar 2024 02:36
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Contributors
Author:
Alice Garrett
Author:
Miranda Durkie
Author:
Alison Callaway
Author:
George J. Burghel
Author:
Rachel Robinson
Author:
James Drummond
Author:
Bethany Torr
Author:
Cankut Cubuk
Author:
Ian R. Berry
Author:
Andrew J. Wallace
Author:
Sian Ellard
Author:
Marc Tischkowitz
Author:
Helen Hanson
Author:
Clare Turnbull
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