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An optimized protocol for evaluating pathogenicity of VHL germline variants in patients suspected with von Hippel-Lindau syndrome: Using somatic genome to inform the role of germline variants

The interpretation of hereditary genetic sequencing variants is often limited due to the absence of functional data and other key evidence to assess the role of variants in disease. Cancer genetics is unique, as two sets of genomic information are often available from a cancer patient: somatic and g...

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Autores principales: Koeller, Diane R., Manning, Danielle K., Schwartz, Alison, Chittenden, Anu, Hayes, Connor P., Abraamyan, Feruza, Rana, Huma Q., Lindeman, Neal I., Garber, Judy E., Ghazani, Arezou A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9237939/
https://www.ncbi.nlm.nih.gov/pubmed/35774415
http://dx.doi.org/10.1016/j.mex.2022.101761
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author Koeller, Diane R.
Manning, Danielle K.
Schwartz, Alison
Chittenden, Anu
Hayes, Connor P.
Abraamyan, Feruza
Rana, Huma Q.
Lindeman, Neal I.
Garber, Judy E.
Ghazani, Arezou A.
author_facet Koeller, Diane R.
Manning, Danielle K.
Schwartz, Alison
Chittenden, Anu
Hayes, Connor P.
Abraamyan, Feruza
Rana, Huma Q.
Lindeman, Neal I.
Garber, Judy E.
Ghazani, Arezou A.
author_sort Koeller, Diane R.
collection PubMed
description The interpretation of hereditary genetic sequencing variants is often limited due to the absence of functional data and other key evidence to assess the role of variants in disease. Cancer genetics is unique, as two sets of genomic information are often available from a cancer patient: somatic and germline. Despite the progress made in the integrated analysis of somatic and germline findings, the assessment of pathogenicity of germline variants in high penetrance genes remains grossly underutilized. Indeed, standard ACMG/AMP guidelines for interpreting germline sequence variants do not address the evidence derived from tumor data in cancer. Previously, we have demonstrated the utility of somatic tumor data as supporting evidence to elucidate the role of germline variants in patients suspected with VHL syndrome and other cancers. We have leveraged the key elements of cancer genetics in these cases: genes with expected high disease penetrance and those with a known biallelic mechanism of tumorigenicity. Here we provide our optimized protocol for evaluating the pathogenicity of germline VHL variants using informative somatic profiling data. This protocol provides details of case selection, assessment of personal and family evidence, somatic tumor profiles, and loss of heterozygosity (LOH) as supporting evidence for the re-evaluation of germline variants.
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spelling pubmed-92379392022-06-29 An optimized protocol for evaluating pathogenicity of VHL germline variants in patients suspected with von Hippel-Lindau syndrome: Using somatic genome to inform the role of germline variants Koeller, Diane R. Manning, Danielle K. Schwartz, Alison Chittenden, Anu Hayes, Connor P. Abraamyan, Feruza Rana, Huma Q. Lindeman, Neal I. Garber, Judy E. Ghazani, Arezou A. MethodsX Protocol Article The interpretation of hereditary genetic sequencing variants is often limited due to the absence of functional data and other key evidence to assess the role of variants in disease. Cancer genetics is unique, as two sets of genomic information are often available from a cancer patient: somatic and germline. Despite the progress made in the integrated analysis of somatic and germline findings, the assessment of pathogenicity of germline variants in high penetrance genes remains grossly underutilized. Indeed, standard ACMG/AMP guidelines for interpreting germline sequence variants do not address the evidence derived from tumor data in cancer. Previously, we have demonstrated the utility of somatic tumor data as supporting evidence to elucidate the role of germline variants in patients suspected with VHL syndrome and other cancers. We have leveraged the key elements of cancer genetics in these cases: genes with expected high disease penetrance and those with a known biallelic mechanism of tumorigenicity. Here we provide our optimized protocol for evaluating the pathogenicity of germline VHL variants using informative somatic profiling data. This protocol provides details of case selection, assessment of personal and family evidence, somatic tumor profiles, and loss of heterozygosity (LOH) as supporting evidence for the re-evaluation of germline variants. Elsevier 2022-06-18 /pmc/articles/PMC9237939/ /pubmed/35774415 http://dx.doi.org/10.1016/j.mex.2022.101761 Text en © 2022 The Authors. Published by Elsevier B.V. https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Protocol Article
Koeller, Diane R.
Manning, Danielle K.
Schwartz, Alison
Chittenden, Anu
Hayes, Connor P.
Abraamyan, Feruza
Rana, Huma Q.
Lindeman, Neal I.
Garber, Judy E.
Ghazani, Arezou A.
An optimized protocol for evaluating pathogenicity of VHL germline variants in patients suspected with von Hippel-Lindau syndrome: Using somatic genome to inform the role of germline variants
title An optimized protocol for evaluating pathogenicity of VHL germline variants in patients suspected with von Hippel-Lindau syndrome: Using somatic genome to inform the role of germline variants
title_full An optimized protocol for evaluating pathogenicity of VHL germline variants in patients suspected with von Hippel-Lindau syndrome: Using somatic genome to inform the role of germline variants
title_fullStr An optimized protocol for evaluating pathogenicity of VHL germline variants in patients suspected with von Hippel-Lindau syndrome: Using somatic genome to inform the role of germline variants
title_full_unstemmed An optimized protocol for evaluating pathogenicity of VHL germline variants in patients suspected with von Hippel-Lindau syndrome: Using somatic genome to inform the role of germline variants
title_short An optimized protocol for evaluating pathogenicity of VHL germline variants in patients suspected with von Hippel-Lindau syndrome: Using somatic genome to inform the role of germline variants
title_sort optimized protocol for evaluating pathogenicity of vhl germline variants in patients suspected with von hippel-lindau syndrome: using somatic genome to inform the role of germline variants
topic Protocol Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9237939/
https://www.ncbi.nlm.nih.gov/pubmed/35774415
http://dx.doi.org/10.1016/j.mex.2022.101761
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