Consistency of variant interpretations among bioinformaticians and clinical geneticists in hereditary cancer panels

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dc.authoriddoğan, özlem/0000-0002-8310-4053
dc.authoridAgaoglu, Nihat Bugra/0000-0002-9336-0552
dc.authoridTemel, Sehime G/0000-0002-9802-0880
dc.authorwosiddoğan, özlem/ABI-7733-2020
dc.authorwosidAgaoglu, Nihat Bugra/Q-3142-2019
dc.contributor.authorAgaoglu, Nihat Bugra
dc.contributor.authorUnal, Busra
dc.contributor.authorDogan, Ozlem Akgun
dc.contributor.authorKanev, Martin Orlinov
dc.contributor.authorZolfagharian, Payam
dc.contributor.authorSag, Sebnem Ozemri
dc.contributor.authorTemel, Sehime Gulsun
dc.date.accessioned2024-06-12T11:19:13Z
dc.date.available2024-06-12T11:19:13Z
dc.date.issued2022
dc.departmentTrakya Üniversitesien_US
dc.description.abstractNext-generation sequencing (NGS) is used increasingly in hereditary cancer patients' (HCP) management. While enabling evaluation of multiple genes simultaneously, the technology brings to light the dilemma of variant interpretation. Here, we aimed to reveal the underlying reasons for the discrepancy in the evidence titles used during variant classification according to ACMG guidelines by two different bioinformatic specialists (BIs) and two different clinical geneticists (CGs). We evaluated final reports of 1920 cancer patients and 189 different variants from 285 HCP were enrolled to the study. A total of 173 of these variants were classified as pathogenic (n = 132) and likely pathogenic (n = 41) by the BI and an additional 16 variants, that were classified as VUS by at least one interpreter and their classification would change the clinical management, were compared for their evidence titles between different specialists. The attributed evidence titles and the final classification of the variants among BIs and CGs were compared. The discrepancy between P/LP final reports was 22.5%. The discordance between CGs was 30% whereas the discordance between two BIs was almost 75%. The use of PVS1, PS3, PP3, PP5, PM1, PM2, BP1, BP4 criteria markedly varied from one expert to another. This difference was particularly noticeable in PP3, PP5, and PM1 evidence and mostly in the variants affecting splice sites like BRCA1(NM_007294.4) c.4096 + 1 G > A and CHEK2(NM_007194.4) c.592 + 3 A > T. With recent advancements in precision medicine, the importance of variant interpretations is emerging. Our study shows that variant interpretation is subjective process that is in need of concrete definitions for accurate and standard interpretation.en_US
dc.description.sponsorshipIstanbul Development Agency (IDA) [YNY2016/144]en_US
dc.description.sponsorshipThis study was partially supported by Istanbul Development Agency (IDA) project number YNY2016/144.en_US
dc.identifier.doi10.1038/s41431-022-01060-7
dc.identifier.endpage383en_US
dc.identifier.issn1018-4813
dc.identifier.issn1476-5438
dc.identifier.issue3en_US
dc.identifier.pmid35132179en_US
dc.identifier.scopus2-s2.0-85124340461en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage378en_US
dc.identifier.urihttps://doi.org/10.1038/s41431-022-01060-7
dc.identifier.urihttps://hdl.handle.net/20.500.14551/25123
dc.identifier.volume30en_US
dc.identifier.wosWOS:000752173700001en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherSpringernatureen_US
dc.relation.ispartofEuropean Journal Of Human Geneticsen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectJoint-Consensus-Recommendationen_US
dc.subjectSequence Variantsen_US
dc.subjectBrca1en_US
dc.subjectGuidelinesen_US
dc.subjectLaboratoriesen_US
dc.subjectAssociationen_US
dc.subjectStandardsen_US
dc.subjectCollegeen_US
dc.subjectGenesen_US
dc.titleConsistency of variant interpretations among bioinformaticians and clinical geneticists in hereditary cancer panelsen_US
dc.typeArticleen_US

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