link<\/a><\/p>\nAbstract:<\/p>\n
Current BRCA1<\/em> and BRCA2<\/em> genetic testing for hereditary breast and ovarian cancer (HBOC) is often\u00a0uninformative. The \u201cmissing heritability\u201d may be due to variants in uninvestigated regions of these genes or\u00a0variants in other genes. We have applied a unified framework based on information theory (IT) to predict and\u00a0prioritize non-coding variants of uncertain significance. We captured complete gene sequences of 21 diseaserelevant genes in HBOC patients with uninformative hereditary predisposition testing (N=336) by hybridization\u00a0enrichment using ab initio<\/em> single copy probes that comprehensively span non-coding regions and flanking\u00a0sequences of ATM, ATP8B1, BARD1, BRCA1, BRCA2, CDH1, CHEK2, EPCAM, MLH1, MRE11A, MSH2, MSH6,\u00a0MUTYH, NBN, PALB2, PMS2, PTEN, RAD51B, STK11, TP53, and XRCC2<\/em>. We identified 38,538 unique variants.\u00a0Eight were likely pathogenic BRCA1\/2 mutations previously undetected by clinical testing. Eight proteintruncating mutations were identified in non-BRCA genes, the majority of which were in PALB2 (N=5), and 148\u00a0missense variants were flagged. Information weight matrices were derived for transcription factor (TFBS),\u00a0splicing regulatory (SRBS), and RNA-binding (RBBS) protein binding sites from high-throughput sequencing\u00a0data. IT analysis prioritized 12 variants affecting splicing (6 natural, 6 cryptic), 71 TFBS, 218 SRBS, and 29\u00a0RBBS. Co-segregation analysis found the relative risk of breast cancer for likely pathogenic BRCA variants torange from 1.55 to 75.78. According to clinically accepted guidelines, twenty-three were possibly pathogenic\u00a0(13 confirmed by Sanger sequencing to date), 472 were of uncertain significance, and all remaining were likely\u00a0not pathogenic. Complete gene analysis of BRCA1\/2<\/em> and other genes is a successful strategy for identifying\u00a0probable mutations in previously uninformative HBOC patients.<\/p>\n","protected":false},"excerpt":{"rendered":"Peter Rogan will be presenting: Seeking the \u201cMissing Heritability\u201d in High-Risk Hereditary Breast and Ovarian Cancer (HBOC) Patients By Prioritizing Coding and Non-Coding Variants in 21 Genes. \u00a0Natasha Caminsky G,\u00a0Eliseos Mucaki J, \u00a0Amelia Perri M,\u00a0Ruipeng Lu,\u00a0Matthew Halvorsen,\u00a0Alain Laederach,\u00a0Joan Knoll HM,\u00a0Peter Rogan K on Tuesday, November 10 from 12-2 PM in the poster session:\u00a0Genomics, Proteomics, and […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":[],"categories":[6],"tags":[],"_links":{"self":[{"href":"https:\/\/www.cytognomix.com\/index.php?rest_route=\/wp\/v2\/posts\/3788"}],"collection":[{"href":"https:\/\/www.cytognomix.com\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.cytognomix.com\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.cytognomix.com\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.cytognomix.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=3788"}],"version-history":[{"count":4,"href":"https:\/\/www.cytognomix.com\/index.php?rest_route=\/wp\/v2\/posts\/3788\/revisions"}],"predecessor-version":[{"id":3794,"href":"https:\/\/www.cytognomix.com\/index.php?rest_route=\/wp\/v2\/posts\/3788\/revisions\/3794"}],"wp:attachment":[{"href":"https:\/\/www.cytognomix.com\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=3788"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.cytognomix.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=3788"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.cytognomix.com\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=3788"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}