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Showing content from https://www.ncbi.nlm.nih.gov/pubmed/27621404 below:

Conflicting Interpretation of Genetic Variants and Cancer Risk by Commercial Laboratories as Assessed by the Prospective Registry of Multiplex Testing

Affiliations

• ¹ Judith Balmaña, Hospital Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain; Laura Digiovanni, Susan M. Domchek, and Katherine L. Nathanson, University of Pennsylvania, Philadelphia, PA; Pragna Gaddam, Michael F. Walsh, Vijai Joseph, Zsofia K. Stadler, Kenneth Offit, and Mark E. Robson, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY; Judy E. Garber, Dana-Farber Cancer Institute, Boston, MA; and Fergus J. Couch, Mayo Clinic, Rochester, MN.

• PMID: 27621404
• PMCID: PMC5562435
• DOI: 10.1200/JCO.2016.68.4316

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Judith Balmaña et al. J Clin Oncol. 2016 Dec.

• ¹ Judith Balmaña, Hospital Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain; Laura Digiovanni, Susan M. Domchek, and Katherine L. Nathanson, University of Pennsylvania, Philadelphia, PA; Pragna Gaddam, Michael F. Walsh, Vijai Joseph, Zsofia K. Stadler, Kenneth Offit, and Mark E. Robson, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY; Judy E. Garber, Dana-Farber Cancer Institute, Boston, MA; and Fergus J. Couch, Mayo Clinic, Rochester, MN.

• PMID: 27621404
• PMCID: PMC5562435
• DOI: 10.1200/JCO.2016.68.4316

Item in Clipboard

Purpose Massively parallel sequencing allows simultaneous testing of multiple genes associated with cancer susceptibility. Guidelines are available for variant classification; however, interpretation of these guidelines by laboratories and providers may differ and lead to conflicting reporting and, potentially, to inappropriate medical management. We describe conflicting variant interpretations between Clinical Laboratory Improvement Amendments-approved commercial clinical laboratories, as reported to the Prospective Registry of Multiplex Testing (PROMPT), an online genetic registry. Methods Clinical data and genetic testing results were gathered from 1,191 individuals tested for inherited cancer susceptibility and self-enrolled in PROMPT between September 2014 and October 2015. Overall, 518 participants (603 genetic variants) had a result interpreted by more than one laboratory, including at least one submitted to ClinVar, and these were used as the final cohort for the current analysis. Results Of the 603 variants, 221 (37%) were classified as a variant of uncertain significance (VUS), 191 (32%) as pathogenic, and 34 (6%) as benign. The interpretation differed among reporting laboratories for 155 (26%). Conflicting interpretations were most frequently reported for CHEK2 and ATM, followed by RAD51C, PALB2, BARD1, NBN, and BRIP1. Among all participants, 56 of 518 (11%) had a variant with conflicting interpretations ranging from pathogenic/likely pathogenic to VUS, a discrepancy that may alter medical management. Conclusions Conflicting interpretation of genetic findings from multiplex panel testing used in clinical practice is frequent and may have implications for medical management decisions.

PubMed Disclaimer

Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org . Author contributions are found at the end of this article.

CONSORT diagram showing the flow…

CONSORT diagram showing the flow of participants and genetic variants per participant from…

CONSORT diagram showing the flow of participants and genetic variants per participant from the PROMPT registry until inclusion for current analysis. PROMPT, Prospective Registry of Multiplex Testing.

Distribution of genetic variants with…

Distribution of genetic variants with multiple submissions in ClinVar by gene (N =…

Distribution of genetic variants with multiple submissions in ClinVar by gene (N = 603).

Distribution of genetic variants according…

Distribution of genetic variants according to ClinVar interpretation (N = 603), and the…

Distribution of genetic variants according to ClinVar interpretation (N = 603), and the absolute number of variants with conflicting interpretation by gene (n = 155).

Type of conflicting interpretation by…

Type of conflicting interpretation by genes.

Type of conflicting interpretation by genes.

• Reply to R.L. Nussbaum et al and J.S. Dolinsky et al.

  Balmaña J, Nathanson K, Offit K, Robson M, Domchek S. Balmaña J, et al. J Clin Oncol. 2017 Apr 10;35(11):1262-1263. doi: 10.1200/JCO.2016.71.3859. Epub 2017 Jan 30. J Clin Oncol. 2017. PMID: 28135137 No abstract available.

• Clinical implications of conflicting variant interpretations in the cancer genetics clinic.

  Zukin E, Culver JO, Liu Y, Yang Y, Ricker CN, Hodan R, Sturgeon D, Kingham K, Chun NM, Rowe-Teeter C, Singh K, Zell JA, Ladabaum U, McDonnell KJ, Ford JM, Parmigiani G, Braun D, Kurian AW, Gruber SB, Idos GE. Zukin E, et al. Genet Med. 2023 Jul;25(7):100837. doi: 10.1016/j.gim.2023.100837. Epub 2023 Apr 11. Genet Med. 2023. PMID: 37057674 Free PMC article.

• Optimising clinical care through CDH1-specific germline variant curation: improvement of clinical assertions and updated curation guidelines.

  Luo X, Maciaszek JL, Thompson BA, Leong HS, Dixon K, Sousa S, Anderson M, Roberts ME, Lee K, Spurdle AB, Mensenkamp AR, Brannan T, Pardo C, Zhang L, Pesaran T, Wei S, Fasaye GA, Kesserwan C, Shirts BH, Davis JL, Oliveira C, Plon SE, Schrader KA, Karam R; ClinGen CDH1 Variant Curation Expert Panel. Luo X, et al. J Med Genet. 2023 Jun;60(6):568-575. doi: 10.1136/jmg-2022-108807. Epub 2022 Dec 7. J Med Genet. 2023. PMID: 36600593 Free PMC article.

• Does multilocus inherited neoplasia alleles syndrome have severe clinical expression?

  Stradella A, Del Valle J, Rofes P, Feliubadaló L, Grau Garces È, Velasco À, González S, Vargas G, Izquierdo Á, Campos O, Tornero E, Navarro M, Balmaña-Gelpi J, Capellá G, Pineda M, Brunet J, Lázaro C. Stradella A, et al. J Med Genet. 2019 Aug;56(8):521-525. doi: 10.1136/jmedgenet-2018-105700. Epub 2018 Dec 22. J Med Genet. 2019. PMID: 30580288 Free PMC article.

• BRCA1 Norway: comparison of classification for BRCA1 germline variants detected in families with suspected hereditary breast and ovarian cancer between different laboratories.

  Hovland HN, Al-Adhami R, Ariansen SL, Van Ghelue M, Sjursen W, Lima S, Bolstad M, Berger AH, Høberg-Vetti H, Knappskog P, Haukanes BI, Aukrust I, Ognedal E. Hovland HN, et al. Fam Cancer. 2022 Oct;21(4):389-398. doi: 10.1007/s10689-021-00286-6. Epub 2022 Jan 4. Fam Cancer. 2022. PMID: 34981296 Free PMC article.

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