Understanding variants of unknown significance and classification of genomic alterations
Despite recent efforts to issue clinical guidelines outlining strategies to define the pathogenicity of genomic variants, there is currently no standardized framework for which to make these assertions. This review does not present a step-by-step methodology, but rather takes a holistic approach to...
Saved in:
| Published in | The oncologist (Dayton, Ohio) Vol. 29; no. 8; pp. 658 - 666 |
|---|---|
| Main Authors | , , |
| Format | Journal Article |
| Language | English |
| Published |
England
Oxford University Press
05.08.2024
|
| Subjects | |
| Online Access | Get full text |
Cover
Loading…
| Abstract | Despite recent efforts to issue clinical guidelines outlining strategies to define the pathogenicity of genomic variants, there is currently no standardized framework for which to make these assertions. This review does not present a step-by-step methodology, but rather takes a holistic approach to discuss many aspects which should be taken into consideration when determining variant pathogenicity. Categorization should be curated to reflect relevant findings within the scope of the specific medical context. Functional characterization should evaluate all available information, including results from literature reviews, different classes of genomic data repositories, and applicable computational predictive algorithms. This article further proposes a multidimensional view to infer pathogenic status from many genomic measurements across multiple axes. Notably, tumor suppressors and oncogenes exhibit fundamentally different biology which helps refine the importance of effects on splicing, mutation interactions, copy number thresholds, rearrangement annotations, germline status, and genome-wide signatures. Understanding these relevant datapoints with thoughtful perspective could aid in the reclassification of variants of unknown significance (VUS), which are ambiguously understood and currently have uncertain clinical implications. Ongoing assessments of VUS examining these relevant biological axes could lead to more accurate classification of variant pathogenicity interpretation in diagnostic oncology. |
|---|---|
| AbstractList | Abstract Despite recent efforts to issue clinical guidelines outlining strategies to define the pathogenicity of genomic variants, there is currently no standardized framework for which to make these assertions. This review does not present a step-by-step methodology, but rather takes a holistic approach to discuss many aspects which should be taken into consideration when determining variant pathogenicity. Categorization should be curated to reflect relevant findings within the scope of the specific medical context. Functional characterization should evaluate all available information, including results from literature reviews, different classes of genomic data repositories, and applicable computational predictive algorithms. This article further proposes a multidimensional view to infer pathogenic status from many genomic measurements across multiple axes. Notably, tumor suppressors and oncogenes exhibit fundamentally different biology which helps refine the importance of effects on splicing, mutation interactions, copy number thresholds, rearrangement annotations, germline status, and genome-wide signatures. Understanding these relevant datapoints with thoughtful perspective could aid in the reclassification of variants of unknown significance (VUS), which are ambiguously understood and currently have uncertain clinical implications. Ongoing assessments of VUS examining these relevant biological axes could lead to more accurate classification of variant pathogenicity interpretation in diagnostic oncology. Despite recent efforts to issue clinical guidelines outlining strategies to define the pathogenicity of genomic variants, there is currently no standardized framework for which to make these assertions. This review does not present a step-by-step methodology, but rather takes a holistic approach to discuss many aspects which should be taken into consideration when determining variant pathogenicity. Categorization should be curated to reflect relevant findings within the scope of the specific medical context. Functional characterization should evaluate all available information, including results from literature reviews, different classes of genomic data repositories, and applicable computational predictive algorithms. This article further proposes a multidimensional view to infer pathogenic status from many genomic measurements across multiple axes. Notably, tumor suppressors and oncogenes exhibit fundamentally different biology which helps refine the importance of effects on splicing, mutation interactions, copy number thresholds, rearrangement annotations, germline status, and genome-wide signatures. Understanding these relevant datapoints with thoughtful perspective could aid in the reclassification of variants of unknown significance (VUS), which are ambiguously understood and currently have uncertain clinical implications. Ongoing assessments of VUS examining these relevant biological axes could lead to more accurate classification of variant pathogenicity interpretation in diagnostic oncology. Key words: pathogenicity; genomic variant; variants of unknown significance. Despite recent efforts to issue clinical guidelines outlining strategies to define the pathogenicity of genomic variants, there is currently no standardized framework for which to make these assertions. This review does not present a step-by-step methodology, but rather takes a holistic approach to discuss many aspects which should be taken into consideration when determining variant pathogenicity. Categorization should be curated to reflect relevant findings within the scope of the specific medical context. Functional characterization should evaluate all available information, including results from literature reviews, different classes of genomic data repositories, and applicable computational predictive algorithms. This article further proposes a multidimensional view to infer pathogenic status from many genomic measurements across multiple axes. Notably, tumor suppressors and oncogenes exhibit fundamentally different biology which helps refine the importance of effects on splicing, mutation interactions, copy number thresholds, rearrangement annotations, germline status, and genome-wide signatures. Understanding these relevant datapoints with thoughtful perspective could aid in the reclassification of variants of unknown significance (VUS), which are ambiguously understood and currently have uncertain clinical implications. Ongoing assessments of VUS examining these relevant biological axes could lead to more accurate classification of variant pathogenicity interpretation in diagnostic oncology.Despite recent efforts to issue clinical guidelines outlining strategies to define the pathogenicity of genomic variants, there is currently no standardized framework for which to make these assertions. This review does not present a step-by-step methodology, but rather takes a holistic approach to discuss many aspects which should be taken into consideration when determining variant pathogenicity. Categorization should be curated to reflect relevant findings within the scope of the specific medical context. Functional characterization should evaluate all available information, including results from literature reviews, different classes of genomic data repositories, and applicable computational predictive algorithms. This article further proposes a multidimensional view to infer pathogenic status from many genomic measurements across multiple axes. Notably, tumor suppressors and oncogenes exhibit fundamentally different biology which helps refine the importance of effects on splicing, mutation interactions, copy number thresholds, rearrangement annotations, germline status, and genome-wide signatures. Understanding these relevant datapoints with thoughtful perspective could aid in the reclassification of variants of unknown significance (VUS), which are ambiguously understood and currently have uncertain clinical implications. Ongoing assessments of VUS examining these relevant biological axes could lead to more accurate classification of variant pathogenicity interpretation in diagnostic oncology. Despite recent efforts to issue clinical guidelines outlining strategies to define the pathogenicity of genomic variants, there is currently no standardized framework for which to make these assertions. This review does not present a step-by-step methodology, but rather takes a holistic approach to discuss many aspects which should be taken into consideration when determining variant pathogenicity. Categorization should be curated to reflect relevant findings within the scope of the specific medical context. Functional characterization should evaluate all available information, including results from literature reviews, different classes of genomic data repositories, and applicable computational predictive algorithms. This article further proposes a multidimensional view to infer pathogenic status from many genomic measurements across multiple axes. Notably, tumor suppressors and oncogenes exhibit fundamentally different biology which helps refine the importance of effects on splicing, mutation interactions, copy number thresholds, rearrangement annotations, germline status, and genome-wide signatures. Understanding these relevant datapoints with thoughtful perspective could aid in the reclassification of variants of unknown significance (VUS), which are ambiguously understood and currently have uncertain clinical implications. Ongoing assessments of VUS examining these relevant biological axes could lead to more accurate classification of variant pathogenicity interpretation in diagnostic oncology. Despite recent efforts to issue clinical guidelines outlining strategies to define the pathogenicity of genomic variants, there is currently no standardized framework for which to make these assertions. This review does not present a step-by-step methodology, but rather takes a holistic approach to discuss many aspects which should be taken into consideration when determining variant pathogenicity. Categorization should be curated to reflect relevant findings within the scope of the specific medical context. Functional characterization should evaluate all available information, including results from literature reviews, different classes of genomic data repositories, and applicable computational predictive algorithms. This article further proposes a multidimensional view to infer pathogenic status from many genomic measurements across multiple axes. Notably, tumor suppressors and oncogenes exhibit fundamentally different biology which helps refine the importance of effects on splicing, mutation interactions, copy number thresholds, rearrangement annotations, germline status, and genome-wide signatures. Understanding these relevant datapoints with thoughtful perspective could aid in the reclassification of variants of unknown significance (VUS), which are ambiguously understood and currently have uncertain clinical implications. Ongoing assessments of VUS examining these relevant biological axes could lead to more accurate classification of variant pathogenicity interpretation in diagnostic oncology. This review does not present a step-by-step methodology but, rather, takes a holistic approach to discuss many aspects that should be taken into consideration when determining variant pathogenicity. |
| Audience | Professional Academic |
| Author | Pavlick, Dean C Ross, Jeffrey R Frampton, Garrett M |
| Author_xml | – sequence: 1 givenname: Dean C surname: Pavlick fullname: Pavlick, Dean C organization: Department of Computational Discovery, Foundation Medicine, Inc., Boston, MA, United States – sequence: 2 givenname: Garrett M surname: Frampton fullname: Frampton, Garrett M organization: Department of Computational Discovery, Foundation Medicine, Inc., Boston, MA, United States – sequence: 3 givenname: Jeffrey R surname: Ross fullname: Ross, Jeffrey R organization: Departments of Pathology, Medicine (Oncology), and Urology, Upstate Medical University, Syracuse, NY, United States |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/38982622$$D View this record in MEDLINE/PubMed |
| BookMark | eNptkc9rFTEQx4NU7A-9epQFL162TXb2R3KSUmwVCl4s9BbmJZM1um9SN_sq_e_N63sWhZJDhu985ksy32NxwIlJiLdKnipp4CyxS1M6Sw9IqjUvxJHqWlO3Rt4elFpqqAfVmUNxnPMPKUsJzStxCNropm-aI3F7w57mvCD7yGN1j3NEXnKVQrXhn5x-c5XjyDFEh-yoKlzlJsz5UVli4i06Eqd1dBVOC82Pan4tXgacMr3Z3yfi5vLTt4vP9fXXqy8X59e1AwlL7VCB1qQI_GolUTXOoTe-N60PstdKa1DKdytQQbVEAQYMEKDDpvMAnYMT8XHne7dZrck74mXGyd7NcY3zg00Y7f8djt_tmO6tUo0xBkxx-LB3mNOvDeXFrmN2NE3IlDbZghwGY5pWyoK-36EjTmQjh1Qs3Ra351oOXd8bgEKdPkOV46ksqeQXYtGfG3Bzynmm8PR8Je02ZruL2e5jLgPv_v30E_43V_gD2xCqAA |
| Cites_doi | 10.1056/NEJMoa2203690 10.1101/gr.9.8.677 10.1093/nar/gky1015 10.1093/oncolo/oyab053 10.3390/cells9102304 10.1016/S1470-2045(12)70312-1 10.1158/1535-7163.MCT-07-2387 10.1093/oncolo/oyae103 10.1158/2159-8290.CD-15-0285 10.1158/0008-5472.CAN-15-0989 10.1084/jem.20111855 10.3389/fonc.2021.713530 10.1038/s41586-020-2308-7 10.1200/PO.22.00019 10.1371/journal.pcbi.1005965 10.1002/humu.23645 10.1001/jama.2019.3241 10.1016/j.gim.2022.05.002 10.1158/2159-8290.CD-17-0321 10.1158/1538-7445.AM2022-1249 10.1016/j.annonc.2021.09.016 10.1016/j.cell.2018.12.015 10.3390/ijms22115515 10.1093/nar/gkx1153 10.1186/s13059-017-1353-5 10.1038/s41586-021-03819-2 10.1001/jama.2018.13152 10.18632/oncotarget.28376 10.1073/pnas.2000060117 10.1073/pnas.68.4.820 10.1016/j.gim.2022.01.001 10.1093/oncolo/oyae135 10.1186/1471-2407-10-389 10.1093/annonc/mdz136 10.1038/gim.2015.30 10.1016/j.febslet.2006.03.024 10.1186/s13073-017-0424-2 10.1126/science.aam7344 10.1002/path.2632 10.1016/j.jmoldx.2019.06.011 10.1093/jnci/djy075 10.1016/j.jmoldx.2016.10.002 10.1038/ng.3774 |
| ContentType | Journal Article |
| Copyright | The Author(s) 2024. Published by Oxford University Press. COPYRIGHT 2024 Oxford University Press The Author(s) 2024. Published by Oxford University Press. 2024 |
| Copyright_xml | – notice: The Author(s) 2024. Published by Oxford University Press. – notice: COPYRIGHT 2024 Oxford University Press – notice: The Author(s) 2024. Published by Oxford University Press. 2024 |
| DBID | CGR CUY CVF ECM EIF NPM AAYXX CITATION 7X8 5PM |
| DOI | 10.1093/oncolo/oyae149 |
| DatabaseName | Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed CrossRef MEDLINE - Academic PubMed Central (Full Participant titles) |
| DatabaseTitle | MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) CrossRef MEDLINE - Academic |
| DatabaseTitleList | CrossRef MEDLINE - Academic MEDLINE |
| Database_xml | – sequence: 1 dbid: NPM name: PubMed url: https://proxy.k.utb.cz/login?url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: EIF name: MEDLINE url: https://proxy.k.utb.cz/login?url=https://www.webofscience.com/wos/medline/basic-search sourceTypes: Index Database |
| DeliveryMethod | fulltext_linktorsrc |
| Discipline | Medicine |
| EISSN | 1549-490X |
| EndPage | 666 |
| ExternalDocumentID | A807566933 10_1093_oncolo_oyae149 38982622 |
| Genre | Journal Article Review |
| GeographicLocations | United States |
| GeographicLocations_xml | – name: United States |
| GroupedDBID | --- 0R~ 123 18M 1OC 24P 36B 4.4 AAPXW AAVAP AAWTL AAZKR ABPTD ABXVV ADBBV ADXAS AEGXH AENEX ALMA_UNASSIGNED_HOLDINGS AOIJS BAWUL CGR CS3 CUY CVF DCZOG DIK DU5 E3Z EBD EBS ECM EIF EMB EMOBN F5P FRP GROUPED_DOAJ GX1 HYE HZ~ IAO IHR INH ITC LUTES LYRES NPM O9- OK1 P2P P2W RAO RHF RHI ROX RPM SV3 TOX TR2 W2D WIN WOHZO WOQ XSB ZZTAW AAYXX CITATION 7X8 5PM |
| ID | FETCH-LOGICAL-c303t-ca1388e1e3dbb0a12ccad9d694df068188311d5b31f14eef37af3f35a25d335c3 |
| IEDL.DBID | RPM |
| ISSN | 1083-7159 1549-490X |
| IngestDate | Tue Sep 17 21:28:35 EDT 2024 Wed Aug 07 17:00:32 EDT 2024 Thu Sep 12 00:30:49 EDT 2024 Tue Sep 10 03:51:21 EDT 2024 Thu Sep 26 20:50:14 EDT 2024 Wed Oct 02 05:29:09 EDT 2024 |
| IsDoiOpenAccess | true |
| IsOpenAccess | true |
| IsPeerReviewed | true |
| IsScholarly | true |
| Issue | 8 |
| Keywords | variants of unknown significance pathogenicity genomic variant |
| Language | English |
| License | The Author(s) 2024. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
| LinkModel | DirectLink |
| MergedId | FETCHMERGED-LOGICAL-c303t-ca1388e1e3dbb0a12ccad9d694df068188311d5b31f14eef37af3f35a25d335c3 |
| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 ObjectType-Review-3 content type line 23 |
| OpenAccessLink | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11299939/ |
| PMID | 38982622 |
| PQID | 3077992400 |
| PQPubID | 23479 |
| PageCount | 9 |
| ParticipantIDs | pubmedcentral_primary_oai_pubmedcentral_nih_gov_11299939 proquest_miscellaneous_3077992400 gale_infotracmisc_A807566933 gale_infotracacademiconefile_A807566933 crossref_primary_10_1093_oncolo_oyae149 pubmed_primary_38982622 |
| PublicationCentury | 2000 |
| PublicationDate | 2024-Aug-05 |
| PublicationDateYYYYMMDD | 2024-08-05 |
| PublicationDate_xml | – month: 08 year: 2024 text: 2024-Aug-05 day: 05 |
| PublicationDecade | 2020 |
| PublicationPlace | England |
| PublicationPlace_xml | – name: England – name: US |
| PublicationTitle | The oncologist (Dayton, Ohio) |
| PublicationTitleAlternate | Oncologist |
| PublicationYear | 2024 |
| Publisher | Oxford University Press |
| Publisher_xml | – name: Oxford University Press |
| References | Edwards (2024080521155364600_CIT0035) 2010; 220 1000 Genomes Project Consortium (2024080521155364600_CIT0007) 2015; 526 Frampton (2024080521155364600_CIT0025) 2015; 5 Vega (2024080521155364600_CIT0043) 2021; 32 Rivera-Muñoz (2024080521155364600_CIT0045) 2018; 39 Horak (2024080521155364600_CIT0005) 2022; 24 Carneiro (2024080521155364600_CIT0031) 2018; 2 Pan (2024080521155364600_CIT0033) 2021; 11 Ghosh (2024080521155364600_CIT0019) 2017; 18 Zerdan (2024080521155364600_CIT0030) 2023; 14 Modi (2024080521155364600_CIT0034) 2022; 387 Wilson (2024080521155364600_CIT0021) 2006; 580 Swanton (2024080521155364600_CIT0011) 2012; 13 Antonarakis (2024080521155364600_CIT0044) 2022; 82 Li (2024080521155364600_CIT0004) 2017; 19 Richards (2024080521155364600_CIT0002) 2015; 17 Griffith (2024080521155364600_CIT0013) 2017; 49 Spangle (2024080521155364600_CIT0020) 2020; 117 Le Tourneau (2024080521155364600_CIT0015) 2022; 6 Chang (2024080521155364600_CIT0010) 2018; 8 Stewart (2024080521155364600_CIT0042) 2022; 27 Manea (2024080521155364600_CIT0036) 2022; 79 Sherry (2024080521155364600_CIT0008) 1999; 9 Lord (2024080521155364600_CIT0029) 2017; 355 Jumper (2024080521155364600_CIT0017) 2021; 596 Guo (2024080521155364600_CIT0026) 2015; 75 Singal (2024080521155364600_CIT0014) 2019; 321 Plon (2024080521155364600_CIT0046) 2018; 110 Sobhani (2024080521155364600_CIT0027) 2021; 22 Tate (2024080521155364600_CIT0009) 2019; 47 Fostira (2024080521155364600_CIT0024) 2010; 10 Knudson (2024080521155364600_CIT0028) 1971; 68 Chalmers (2024080521155364600_CIT0041) 2017; 9 Parmigiani (2024080521155364600_CIT0022) 2020; 9 Godin-Heymann (2024080521155364600_CIT0032) 2008; 7 Mandelker (2024080521155364600_CIT0037) 2019; 30 Fu (2024080521155364600_CIT0016) 2024 Sun (2024080521155364600_CIT0038) 2018; 14 Loong (2024080521155364600_CIT0003) 2022; 24 Mellgard (2024080521155364600_CIT0001) 2024 Karczewski (2024080521155364600_CIT0006) 2020; 581 Jaiswal (2024080521155364600_CIT0039) 2020; 136 Lobry (2024080521155364600_CIT0023) 2011; 208 Mersch (2024080521155364600_CIT0047) 2018; 320 Landrum (2024080521155364600_CIT0012) 2018; 46 Jaganathan (2024080521155364600_CIT0018) 2019; 176 Trabucco (2024080521155364600_CIT0040) 2019; 21 |
| References_xml | – volume: 387 start-page: 9 issue: 1 year: 2022 ident: 2024080521155364600_CIT0034 article-title: Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer publication-title: N Engl J Med doi: 10.1056/NEJMoa2203690 contributor: fullname: Modi – volume: 9 start-page: 677 issue: 8 year: 1999 ident: 2024080521155364600_CIT0008 article-title: dbSNP - database for single nucleotide polymorphisms and other classes of minor genetic variation publication-title: Genome Res doi: 10.1101/gr.9.8.677 contributor: fullname: Sherry – volume: 47 start-page: D941 issue: D1 year: 2019 ident: 2024080521155364600_CIT0009 article-title: COSMIC: the catalogue of somatic mutations in cancer publication-title: Nucleic Acids Res doi: 10.1093/nar/gky1015 contributor: fullname: Tate – volume: 27 start-page: 167 issue: 3 year: 2022 ident: 2024080521155364600_CIT0042 article-title: Homologous recombination deficiency: Concepts, definitions, and assays publication-title: Oncologist doi: 10.1093/oncolo/oyab053 contributor: fullname: Stewart – volume: 9 start-page: 2304 issue: 10 year: 2020 ident: 2024080521155364600_CIT0022 article-title: Oncogenic and tumor suppressive functions of NOTCH signaling in glioma publication-title: Cells doi: 10.3390/cells9102304 contributor: fullname: Parmigiani – volume: 13 start-page: 668 issue: 7 year: 2012 ident: 2024080521155364600_CIT0011 article-title: My Cancer Genome: a unified genomics and clinical trial portal publication-title: Lancet Oncol doi: 10.1016/S1470-2045(12)70312-1 contributor: fullname: Swanton – volume: 136 start-page: 1606 issue: 14 year: 2020 ident: 2024080521155364600_CIT0039 article-title: Clonal hematopoiesis and nonhematologic disorders publication-title: Blood contributor: fullname: Jaiswal – volume: 7 start-page: 874 issue: 4 year: 2008 ident: 2024080521155364600_CIT0032 article-title: The T790M “gatekeeper” mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitor publication-title: Mol Cancer Ther doi: 10.1158/1535-7163.MCT-07-2387 contributor: fullname: Godin-Heymann – year: 2024 ident: 2024080521155364600_CIT0016 article-title: Understanding variants of unknown significance: the computational frontier publication-title: Oncologist doi: 10.1093/oncolo/oyae103 contributor: fullname: Fu – volume: 5 start-page: 850 issue: 8 year: 2015 ident: 2024080521155364600_CIT0025 article-title: Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors publication-title: Cancer Discov doi: 10.1158/2159-8290.CD-15-0285 contributor: fullname: Frampton – volume: 75 start-page: 3436 issue: 17 year: 2015 ident: 2024080521155364600_CIT0026 article-title: Ligand-independent EGFR signaling publication-title: Cancer Res doi: 10.1158/0008-5472.CAN-15-0989 contributor: fullname: Guo – volume: 208 start-page: 1931 issue: 10 year: 2011 ident: 2024080521155364600_CIT0023 article-title: Oncogenic and tumor suppressor functions of Notch in cancer: it’s NOTCH what you think publication-title: J Exp Med doi: 10.1084/jem.20111855 contributor: fullname: Lobry – volume: 11 start-page: 713530 year: 2021 ident: 2024080521155364600_CIT0033 article-title: The resistance mechanisms and treatment strategies for ALK-rearranged non-small cell lung cancer publication-title: Front Oncol doi: 10.3389/fonc.2021.713530 contributor: fullname: Pan – volume: 581 start-page: 434 issue: 7809 year: 2020 ident: 2024080521155364600_CIT0006 article-title: The mutational constraint spectrum quantified from variation in 141,456 humans publication-title: Nature doi: 10.1038/s41586-020-2308-7 contributor: fullname: Karczewski – volume: 6 start-page: e2200019 year: 2022 ident: 2024080521155364600_CIT0015 article-title: An approach to solving the complex clinicogenomic data landscape in precision oncology: learnings from the design of WAYFIND-R, a global precision oncology registry publication-title: JCO Precis Oncol doi: 10.1200/PO.22.00019 contributor: fullname: Le Tourneau – volume: 14 start-page: e1005965 issue: 2 year: 2018 ident: 2024080521155364600_CIT0038 article-title: A computational approach to distinguish somatic vs. germline origin of genomic alterations from deep sequencing of cancer specimens without a matched normal publication-title: PLoS Comput Biol doi: 10.1371/journal.pcbi.1005965 contributor: fullname: Sun – volume: 39 start-page: 1614 issue: 11 year: 2018 ident: 2024080521155364600_CIT0045 article-title: ClinGen Variant Curation Expert Panel experiences and standardized processes for disease and gene-level specification of the ACMG/AMP guidelines for sequence variant interpretation publication-title: Hum Mutat doi: 10.1002/humu.23645 contributor: fullname: Rivera-Muñoz – volume: 321 start-page: 1391 issue: 14 year: 2019 ident: 2024080521155364600_CIT0014 article-title: Association of patient characteristics and tumor genomics with clinical outcomes among patients with non-small cell lung cancer using a clinicogenomic database publication-title: JAMA doi: 10.1001/jama.2019.3241 contributor: fullname: Singal – volume: 24 start-page: 1867 issue: 9 year: 2022 ident: 2024080521155364600_CIT0003 article-title: Reclassification of clinically-detected sequence variants: Framework for genetic clinicians and clinical scientists by CanVIG-UK (Cancer Variant Interpretation Group UK) publication-title: Genet Med doi: 10.1016/j.gim.2022.05.002 contributor: fullname: Loong – volume: 8 start-page: 174 issue: 2 year: 2018 ident: 2024080521155364600_CIT0010 article-title: Accelerating discovery of functional mutant alleles in cancer publication-title: Cancer Discov doi: 10.1158/2159-8290.CD-17-0321 contributor: fullname: Chang – volume: 82 start-page: 1249 issue: 12_Supplement year: 2022 ident: 2024080521155364600_CIT0044 article-title: Abstract 1249: Development of a pan-cancer algorithm to predict homologous recombination deficiency and sensitivity to PARPi therapy publication-title: Cancer Res doi: 10.1158/1538-7445.AM2022-1249 contributor: fullname: Antonarakis – volume: 32 start-page: 1626 issue: 12 year: 2021 ident: 2024080521155364600_CIT0043 article-title: Aligning tumor mutational burden (TMB) quantification across diagnostic platforms: phase II of the Friends of Cancer Research TMB Harmonization Project publication-title: Ann Oncol doi: 10.1016/j.annonc.2021.09.016 contributor: fullname: Vega – volume: 176 start-page: 535 issue: 3 year: 2019 ident: 2024080521155364600_CIT0018 article-title: Predicting splicing from primary sequence with deep learning publication-title: Cell doi: 10.1016/j.cell.2018.12.015 contributor: fullname: Jaganathan – volume: 22 start-page: 5515 issue: 11 year: 2021 ident: 2024080521155364600_CIT0027 article-title: AR-V7 in metastatic prostate cancer: a strategy beyond redemption publication-title: Int J Mol Sci doi: 10.3390/ijms22115515 contributor: fullname: Sobhani – volume: 46 start-page: D1062 issue: D1 year: 2018 ident: 2024080521155364600_CIT0012 article-title: ClinVar: improving access to variant interpretations and supporting evidence publication-title: Nucleic Acids Res doi: 10.1093/nar/gkx1153 contributor: fullname: Landrum – volume: 18 start-page: 225 issue: 1 year: 2017 ident: 2024080521155364600_CIT0019 article-title: Evaluation of in silico algorithms for use with ACMG/AMP clinical variant interpretation guidelines publication-title: Genome Biol doi: 10.1186/s13059-017-1353-5 contributor: fullname: Ghosh – volume: 79 start-page: 103893 year: 2022 ident: 2024080521155364600_CIT0036 article-title: A review of NTRK fusions in cancer publication-title: Ann Med Surg (Lond) contributor: fullname: Manea – volume: 526 start-page: 68 issue: 7571 year: 2015 ident: 2024080521155364600_CIT0007 article-title: The 1000 Genomes Project Consortium. A global reference for human genetic variation publication-title: Nature contributor: fullname: 1000 Genomes Project Consortium – volume: 596 start-page: 583 issue: 7873 year: 2021 ident: 2024080521155364600_CIT0017 article-title: Highly accurate protein structure prediction with AlphaFold publication-title: Nature doi: 10.1038/s41586-021-03819-2 contributor: fullname: Jumper – volume: 320 start-page: 1266 issue: 12 year: 2018 ident: 2024080521155364600_CIT0047 article-title: Prevalence of variant reclassification following hereditary cancer genetic Testing publication-title: JAMA doi: 10.1001/jama.2018.13152 contributor: fullname: Mersch – volume: 14 start-page: 178 year: 2023 ident: 2024080521155364600_CIT0030 article-title: Genomic landscape of metastatic breast cancer (MBC) patients with methylthioadenosine phosphorylase (MTAP) loss publication-title: Oncotarget doi: 10.18632/oncotarget.28376 contributor: fullname: Zerdan – volume: 117 start-page: 24427 issue: 39 year: 2020 ident: 2024080521155364600_CIT0020 article-title: PIK3CA C-terminal frameshift mutations are novel oncogenic events that sensitize tumors to PI3K-α inhibition publication-title: Proc Natl Acad Sci USA doi: 10.1073/pnas.2000060117 contributor: fullname: Spangle – volume: 2 start-page: PO.17.00176 year: 2018 ident: 2024080521155364600_CIT0031 article-title: Acquired resistance to poly (ADP-ribose) polymerase inhibitor olaparib in BRCA2-associated prostate cancer resulting from biallelic BRCA2 reversion mutations restores both germline and somatic loss-of-function mutations publication-title: JCO Precis Oncol contributor: fullname: Carneiro – volume: 68 start-page: 820 issue: 4 year: 1971 ident: 2024080521155364600_CIT0028 article-title: Mutation and cancer: statistical study of retinoblastoma publication-title: Proc Natl Acad Sci USA doi: 10.1073/pnas.68.4.820 contributor: fullname: Knudson – volume: 24 start-page: 986 issue: 5 year: 2022 ident: 2024080521155364600_CIT0005 article-title: Standards for the classification of pathogenicity of somatic variants in cancer (oncogenicity): joint recommendations of Clinical Genome Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant Interpretation for Cancer Consortium (VICC) publication-title: Genet Med doi: 10.1016/j.gim.2022.01.001 contributor: fullname: Horak – year: 2024 ident: 2024080521155364600_CIT0001 article-title: Variants of uncertain significance (VUS) in precision oncology: nuance or nuisance? publication-title: Oncologist. doi: 10.1093/oncolo/oyae135 contributor: fullname: Mellgard – volume: 10 start-page: 389 year: 2010 ident: 2024080521155364600_CIT0024 article-title: Mutational spectrum of APC and genotype-phenotype correlations in Greek FAP patients publication-title: BMC Cancer doi: 10.1186/1471-2407-10-389 contributor: fullname: Fostira – volume: 30 start-page: 1221 issue: 8 year: 2019 ident: 2024080521155364600_CIT0037 article-title: Germline-focussed analysis of tumour-only sequencing: recommendations from the ESMO Precision Medicine Working Group publication-title: Ann Oncol doi: 10.1093/annonc/mdz136 contributor: fullname: Mandelker – volume: 17 start-page: 405 issue: 5 year: 2015 ident: 2024080521155364600_CIT0002 article-title: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology publication-title: Genet Med doi: 10.1038/gim.2015.30 contributor: fullname: Richards – volume: 580 start-page: 2860 issue: 12 year: 2006 ident: 2024080521155364600_CIT0021 article-title: Multiple functions of Notch signaling in self-renewing organs and cancer publication-title: FEBS Lett doi: 10.1016/j.febslet.2006.03.024 contributor: fullname: Wilson – volume: 9 start-page: 34 issue: 1 year: 2017 ident: 2024080521155364600_CIT0041 article-title: Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden publication-title: Genome Med doi: 10.1186/s13073-017-0424-2 contributor: fullname: Chalmers – volume: 355 start-page: 1152 issue: 6330 year: 2017 ident: 2024080521155364600_CIT0029 article-title: PARP inhibitors: the first synthetic lethal targeted therapy publication-title: Science doi: 10.1126/science.aam7344 contributor: fullname: Lord – volume: 220 start-page: 244 issue: 2 year: 2010 ident: 2024080521155364600_CIT0035 article-title: Fusion genes and chromosome translocations in the common epithelial cancers publication-title: J Pathol doi: 10.1002/path.2632 contributor: fullname: Edwards – volume: 21 start-page: 1053 issue: 6 year: 2019 ident: 2024080521155364600_CIT0040 article-title: A novel next-generation sequencing approach to detecting microsatellite instability and pan-tumor characterization of 1000 microsatellite instability-high cases in 67,000 patient samples publication-title: J Mol Diagn doi: 10.1016/j.jmoldx.2019.06.011 contributor: fullname: Trabucco – volume: 110 start-page: 1133 issue: 10 year: 2018 ident: 2024080521155364600_CIT0046 article-title: The ancestral pace of variant reclassification publication-title: J Natl Cancer Inst doi: 10.1093/jnci/djy075 contributor: fullname: Plon – volume: 19 start-page: 4 issue: 1 year: 2017 ident: 2024080521155364600_CIT0004 article-title: Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists publication-title: J Mol Diagn doi: 10.1016/j.jmoldx.2016.10.002 contributor: fullname: Li – volume: 49 start-page: 170 issue: 2 year: 2017 ident: 2024080521155364600_CIT0013 article-title: CIViC is a community knowledgebase for expert crowdsourcing the clinical interpretation of variants in cancer publication-title: Nat Genet doi: 10.1038/ng.3774 contributor: fullname: Griffith |
| SSID | ssj0015932 |
| Score | 2.4871778 |
| SecondaryResourceType | review_article |
| Snippet | Despite recent efforts to issue clinical guidelines outlining strategies to define the pathogenicity of genomic variants, there is currently no standardized... Abstract Despite recent efforts to issue clinical guidelines outlining strategies to define the pathogenicity of genomic variants, there is currently no... |
| SourceID | pubmedcentral proquest gale crossref pubmed |
| SourceType | Open Access Repository Aggregation Database Index Database |
| StartPage | 658 |
| SubjectTerms | Cancer Cancer Diagnostics and Molecular Pathology Genetic aspects Genetic Variation Genomics - methods Health aspects Humans Identification and classification Mutation Neoplasms - classification Neoplasms - genetics |
| Title | Understanding variants of unknown significance and classification of genomic alterations |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/38982622 https://www.proquest.com/docview/3077992400/abstract/ https://pubmed.ncbi.nlm.nih.gov/PMC11299939 |
| Volume | 29 |
| hasFullText | 1 |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| link | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnV1La-NADBZtD6WXZbuvZtstU1jYk-vY8muOpWwIhbR7aCA343mxgWZS2qS_v9LYDvEeF4PBMzIeJHkkjb7RAPwsmsYk0ujIZVhGjCOMlLFZZJWryN46XQY04ey-mM6zu0W-OICi3wsTQPtaLa_90-raL_8GbOXzSsc9Tiz-M7tlH4HsqowP4bBE7GP0LneQS2xznBVGJT3tSjVivPZcCjqmwNxSZHACx2Suyb9O04FV-ndu3jNOQ-DkniWafIQPnQspbtqhnsKB9Z_geNYlyT_DYr6_YUW8UTTMYBexdmLreQ3NC0ZtMEaIRS6ITmh2okMLC4pJuXjraqlFSKe3y3pfYD75_Xg7jboDFCJNlmkT6SbBqrKJRaPUuElSEpeRppCZceOCTHWFSWJyhYlLMmsdlo1Dh3mT5gYx1_gVjvza2zMQqjQ0F-gy09LxgemVo1BorJWhFrrGI_jVM7B-butk1G1-G-uW63XHdaJk_tb8AxETddPtA6DvcCmq-obLIxeFRBzBxYCSFF8Puq96CdXcxWgxb9fb15rmrVJKRseO4Fsrsd2geomPoBrIckfA9baHPaSGoe52r3bf___VczhJySsKCML8Ao42L1v7g7yajboMqwGXQZXp_viweAdUh_zx |
| link.rule.ids | 230,315,733,786,790,870,891,27957,27958,53827,53829 |
| linkProvider | National Library of Medicine |
| linkToHtml | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnV1Lb9NAEB6VIpVeeD8CBRYJiZPj2OPXHquKKkBTcWhEbivvS40gmwoSDvx6ZvyI4t5APtk7lr2a2Z2ZnW-_BXhf1LVNpDWRz7CMGEcYaeuyyGlfkb_1pmzQhLPLYjrPPi_yxQEU_V6YBrRv9HIcfqzGYXndYCtvVibucWLx19kZxwjkV2V8B-7SgE3LPkvvqge5xLbKWWFU0t2OrBHjdWAy6JhSc0e5wTEckcOmCDtNB37p9uy8556G0Mk9X3T-AL71vWghKN_H240emz-3CB7_vZsP4X4XnorTtv0RHLjwGI5mXQH-CSzm-5thxG_KtBlII9ZebAOvzwXBiBDGH7E5CZIThgP05gkbAYsyMexqaURTqm-XDJ_C_Pzj1dk06g5niAx5vU1k6gSryiUOrdaTOknJFKy0hcysnxQUBlSYJDbXmPgkc85jWXv0mNdpbhFzg8_gMKyDewFCl5bmGVNmRno-jL3ylGZNjLb0hK7JCD70qlE3LQeHamvnqFp9qk6fJMmaUzw4ST2m7vYY0HeY5kqdMvVyUUjEEZwMJGlQmUHzu173ipsYiRbcevtL0ZxYSsnI2xE8b21h91O9LY2gGljJToC5vIctpPuG07vX9cv_f_Ut3JtezS7UxafLL6_gOKXoq0Eq5idwuPm5da8petroN81Q-QuenR0j |
| linkToPdf | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnV1LT9tAEB61IEVcoNAHobRdpEo9OY69fu0R0Ub0EcShkSL1sPK-1AiyiSDhwK9nxo8o5oh8sncsezWzOzM7334L8DUrSxMJowOX8DwgHGGgjE0Cq1yB_tbpvEITjq-yy0nya5pOG1TlfQOr9FrNBv52PvCz_xW2cjnXYYsTC6_HFxQjoF8V4dK48DXs4qCNRZupNxWEVPC60lnwIMe7DWEjDxeeCKFDTM8t5gd70EOnjVF2HHd80_MZestFdeGTW_5odAD_2p7UMJSbwXqlBvrxGcnjy7r6BvabMJWd1zKH8Mr6I-iNm0L8W5hOtjfFsAfMuAlQwxaOrT2t03lGyBDCIZFZMZRjmgL16gkZA4kSQex8pllVsq-XDt_BZPTj78Vl0BzSEGj0fqtAlxEvChtZbpQallGMJmGEyURi3DDDcKDgUWRSxSMXJdY6npeOO56WcWo4TzV_Dzt-4e0xMJUbnG90nmjh6FD2wmG6NdTK4BO8hn341qpHLmsuDlnX0LmsdSobnaIkaU_SIEUV6bLZa4DfIboreU4UzFkmOO_DaUcSB5fuNJ-1-pfURIg0bxfre4lzYy4EIXD78KG2h81PtfbUh6JjKRsB4vTutqD-K27vVt8nL3_1C_Suv4_kn59Xvz_CXoxBWAVYTE9hZ3W3tp8wiFqpz9VoeQJvXh-j |
| openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Understanding+variants+of+unknown+significance+and+classification+of+genomic+alterations&rft.jtitle=The+oncologist+%28Dayton%2C+Ohio%29&rft.au=Pavlick%2C+Dean+C&rft.au=Frampton%2C+Garrett+M&rft.au=Ross%2C+Jeffrey+R&rft.date=2024-08-05&rft.issn=1549-490X&rft.eissn=1549-490X&rft.volume=29&rft.issue=8&rft.spage=658&rft_id=info:doi/10.1093%2Foncolo%2Foyae149&rft.externalDBID=NO_FULL_TEXT |
| thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=1083-7159&client=summon |
| thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=1083-7159&client=summon |
| thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=1083-7159&client=summon |