{"data":{"id":"10.6084/m9.figshare.1632141","type":"dois","attributes":{"doi":"10.6084/m9.figshare.1632141","prefix":"10.6084","suffix":"m9.figshare.1632141","identifiers":[],"alternateIdentifiers":[],"creators":[{"name":"Flower, Kirsty J","nameType":"Personal","givenName":"Kirsty J","familyName":"Flower","affiliation":[],"nameIdentifiers":[]},{"name":"Shenker, Natalie S","nameType":"Personal","givenName":"Natalie S","familyName":"Shenker","affiliation":[],"nameIdentifiers":[]},{"name":"El-Bahrawy, Mona","nameType":"Personal","givenName":"Mona","familyName":"El-Bahrawy","affiliation":[],"nameIdentifiers":[]},{"name":"Goldgar, David E","nameType":"Personal","givenName":"David E","familyName":"Goldgar","affiliation":[],"nameIdentifiers":[]},{"name":"Parsons, Michael T","nameType":"Personal","givenName":"Michael T","familyName":"Parsons","affiliation":[],"nameIdentifiers":[]},{"name":"Spurdle, Amanda B","nameType":"Personal","givenName":"Amanda B","familyName":"Spurdle","affiliation":[],"nameIdentifiers":[]},{"name":"Morris, Joanna R","nameType":"Personal","givenName":"Joanna R","familyName":"Morris","affiliation":[],"nameIdentifiers":[]},{"name":"Brown, Robert","nameType":"Personal","givenName":"Robert","familyName":"Brown","affiliation":[],"nameIdentifiers":[]},{"name":"Flanagan, James M","nameType":"Personal","givenName":"James M","familyName":"Flanagan","affiliation":[],"nameIdentifiers":[]}],"titles":[{"title":"DNA methylation profiling to assess pathogenicity of \u003ci\u003eBRCA1\u003c/i\u003e unclassified variants in breast cancer"}],"publisher":"Taylor \u0026 Francis","container":{},"publicationYear":2015,"subjects":[{"subject":"Space Science"},{"subject":"Medicine"},{"subject":"Cell Biology"},{"subject":"Genetics"},{"subject":"FOS: Biological sciences","schemeUri":"http://www.oecd.org/science/inno/38235147.pdf","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"FOS: Biological sciences","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"Molecular Biology"},{"subject":"Pharmacology"},{"subject":"59999 Environmental Sciences not elsewhere classified","subjectScheme":"FOR"},{"subject":"FOS: Earth and related environmental sciences","schemeUri":"http://www.oecd.org/science/inno/38235147.pdf","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"FOS: Earth and related environmental sciences","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"69999 Biological Sciences not elsewhere classified","subjectScheme":"FOR"},{"subject":"19999 Mathematical Sciences not elsewhere classified","subjectScheme":"FOR"},{"subject":"FOS: Mathematics","schemeUri":"http://www.oecd.org/science/inno/38235147.pdf","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"FOS: Mathematics","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"Cancer"},{"subject":"110309 Infectious Diseases","subjectScheme":"FOR"},{"subject":"FOS: Health sciences","schemeUri":"http://www.oecd.org/science/inno/38235147.pdf","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"FOS: Health sciences","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"Plant Biology"}],"contributors":[],"dates":[{"date":"2016-01-04","dateType":"Created"},{"date":"2017-03-21","dateType":"Updated"},{"date":"2015","dateType":"Issued"}],"language":null,"types":{"ris":"DATA","bibtex":"misc","citeproc":"dataset","schemaOrg":"Dataset","resourceType":"Dataset","resourceTypeGeneral":"Dataset"},"relatedIdentifiers":[{"relationType":"IsSupplementTo","relatedIdentifier":"10.1080/15592294.2015.1111504","relatedIdentifierType":"DOI"}],"relatedItems":[],"sizes":["1312060 Bytes"],"formats":[],"version":null,"rightsList":[{"rights":"Creative Commons Attribution 4.0 International","rightsUri":"https://creativecommons.org/licenses/by/4.0/legalcode","schemeUri":"https://spdx.org/licenses/","rightsIdentifier":"cc-by-4.0","rightsIdentifierScheme":"SPDX"}],"descriptions":[{"description":"Germline pathogenic mutations in \u003ci\u003eBRCA1\u003c/i\u003e increase risk of developing breast cancer. Screening for mutations in \u003ci\u003eBRCA1\u003c/i\u003e frequently identifies sequence variants of unknown pathogenicity and recent work has aimed to develop methods for determining pathogenicity. We previously observed that tumor DNA methylation can differentiate \u003ci\u003eBRCA1\u003c/i\u003e-mutated from \u003ci\u003eBRCA1\u003c/i\u003e-wild type tumors. We hypothesized that we could predict pathogenicity of variants based on DNA methylation profiles of tumors that had arisen in carriers of unclassified variants. We selected 150 FFPE breast tumor DNA samples [47 \u003ci\u003eBRCA1\u003c/i\u003e pathogenic mutation carriers, 65 BRCAx (\u003ci\u003eBRCA1\u003c/i\u003e-wild type), 38 \u003ci\u003eBRCA1\u003c/i\u003e test variants] and analyzed a subset (n=54) using the Illumina 450K methylation platform, using the remaining samples for bisulphite pyrosequencing validation. Three validated markers (\u003ci\u003eBACH2, C8orf31,\u003c/i\u003e and \u003ci\u003eLOC654342\u003c/i\u003e) were combined with sequence bioinformatics in a model to predict pathogenicity of 27 variants (independent test set). Predictions were compared with standard multifactorial likelihood analysis. Prediction was consistent for c.5194-12G\u0026gt;A (IVS 19-12 G\u0026gt;A) (\u003ci\u003eP\u003c/i\u003e\u0026gt;0.99); 13 variants were considered not pathogenic or likely not pathogenic using both approaches. We conclude that tumor DNA methylation data alone has potential to be used in prediction of \u003ci\u003eBRCA1\u003c/i\u003e variant pathogenicity but is not independent of estrogen receptor status and grade, which are used in current multifactorial models to predict pathogenicity.","descriptionType":"Abstract"}],"geoLocations":[],"fundingReferences":[],"xml":"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