[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-351917-105":59,"doc-detail-351917-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","cancer-genetics-report-reclassification-of-a-brca2-variant-case-report","Cancer Genetics Report - Reclassification of a BRCA2 variant - Case report","","A BRCA2 germline synonymous variant, NM_000059.4: c.8487G > A (p.Gln2829Gln), was identified in a Japanese woman with multifocal breast cancer and a strong family history of BRCA2-related malignancies. Although previously classified as a variant of uncertain significance, its position at the 3′ end of exon 19 suggested splicing disruption. In silico analyses predicted altered splicing; absence in population databases supported rarity. RT-PCR showed complete exon 19 skipping, producing an in-frame deletion, consistent with prior minigene data, leading to reclassification as likely pathogenic.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/cancer-genetics-report-reclassification-of-a-brca2-variant-case-report/351917/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/cancer-genetics-report-reclassification-of-a-brca2-variant-case-report/351917.png","ImageObject",300,407,{"name":92,"@type":93},"Mary Man","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-31","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What genetic variant was reclassified in this report?","Question",{"text":112,"@type":113},"The report focuses on the BRCA2 germline synonymous variant NM_000059.4: c.8487G > A (p.Gln2829Gln). It was reclassified from variant of uncertain significance to likely pathogenic based on splicing alteration.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Why did the authors suspect the variant was pathogenic despite being synonymous?",{"text":117,"@type":113},"The variant is located at the 3′ end of exon 19, a region where changes can affect mRNA splicing. The authors expected that splicing might be disrupted by the nucleotide change.",{"name":119,"@type":110,"acceptedAnswer":120},"How was the splicing effect demonstrated?",{"text":121,"@type":113},"RT-PCR using total RNA from the patient’s peripheral blood cells showed skipping of the entire exon 19, resulting in an in-frame deletion. This matched previous in vitro minigene assay observations.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},351917,1790143678,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":24,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":144},7421720224475,"https://ap-avatar.wpscdn.com/davatar_276721f389ce27ea32af1340a28f341c","Japanese Journal of Clinical Oncology, 2026, 56(7), 899–903 [https://doi.org/10.1093/jjco/hyag047](https://doi.org/10.1093/jjco/hyag047)  \n[Published: 18 March 2026](Published: 18 March 2026)  \nCancer Genetics Report  \n| Reclassification of a BRCA2 variant, c.8487G > A (p.Gln2829Gln) located at 3􀀂 end of exon 19, from uncertain significance to likely pathogenic based on splicing alteration: a case report\u003Cbr>Ritsuko Sasaki1 ,2 , Hidetaka Eguchi3 , Sayaka Yoshioka3 , Satoko Nakano4 , Shunsuke Kato4 ,5 , Tomoyuki Aruga2 , Goro Kutomi1 , Masami Arai1 , 6 , * |  |\n| --- | --- |\n| 1 Department of Breast Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan\u003Cbr>2 Department of Breast Surgery, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan\u003Cbr>3 Department of Diagnostics and Therapeutics of Intractable Diseases/Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, 2 1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan\u003Cbr>4 Department of Breast Surgery, Kawaguchi Municipal Medical Center, 180 Nishi-araishuku, Kawaguchi, Saitama 333-0833, Japan\u003Cbr>5 Department of Medical Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan\u003Cbr>6 Department of Clinical Genetics, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo 113-8421, Japan\u003Cbr>*Corresponding author. Department of Clinical Genetics, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo 113-8421, Japan. [E mail: ms-arai@juntendo.ac.jp](E mail: ms-arai@juntendo.ac.jp)\u003Cbr>Abstract\u003Cbr>A BRCA2 germline variant, NM_ 000059.4: c.8487G > A (p.Gln2829Gln), was identified in a Japanese female with multifocal breast cancer and a notable family history of BRCA2-related cancers. While this synonymous variant was reported as a variant of uncertain significance, we suspected its pathogenicity considering its location atthe 3􀀂 end of exon 19. This variant is absent in gnomAD and extremely rare in ToMMojMorp 61KJPN database, with an allelic frequency of 0.000008. All three insilico tools predicted a splicing defect. RT-PCR analysis using total RNA extracted from the patient’s peripheral blood cells demonstrated skipping of entire exon 19, resulting in in-frame deletion. This observation was consistent with a previous report of in vitro minigene assay. The exon 19 encodes 52 amino acids within the single-stranded DNA oligonucleotide/oligosaccharide-binding domain, and thus the in-frame deletion was predicted to impair BRCA2 function. Collectively, we re-classified this variant as likely pathogenic.\u003Cbr>Keywords breast cancer, BRCA2, variant of uncertain significance, splicing site, synonymous variant, in-frame deletion, exon skipping |  |\n| Introduction\u003Cbr>Identification of a pathogenic variant through BRCA1/2 genetic testing (BRACAnalysis®) is crucial not only for guiding the medical management of the affected individual, but also for informing risk assessment and preventive strategies among family members. However, the frequency of variants of uncertain significance (VUS) has been reported to be approximately 7% worldwide [1], posing challenges in clinical decision-making, including uncertainty in surgical choices, risk-reducing strategies, and cascade testing for relatives. In our institute, VUS was identified in 20 out of 569 breast cancer patients (3.5%) who satisfied the criteria for the indication of medical insurance and who underwent BRACAnalysis® . While VUS are often managed as likely benign, we have encountered | cases exhibiting clinical features suggestive of hereditary breast and ovarian cancer (HBOC) syndromes in which transcript-level analysis has revealed the variant to be pathogenic.\u003Cbr>In this report, we found a case that possessed a synonymous variant, BRCA2: NM_ 000059.4:c.8487G > A (p.Gln2829Gln) reported as VUS from the clinical laboratory, Myriad Genetics Inc. However, since this variant was l","cbCainjpvVaH31bw","https://ap.wps.com/l/cbCainjpvVaH31bw","pdf",850567,"English","# Introduction\n# Case presentation\n## Clinical history\n## Variant analysis and splicing evidence","[{\"question\":\"What genetic variant was reclassified in this report?\",\"answer\":\"The report focuses on the BRCA2 germline synonymous variant NM_000059.4: c.8487G \\u003e A (p.Gln2829Gln). It was reclassified from variant of uncertain significance to likely pathogenic based on splicing alteration.\"},{\"question\":\"Why did the authors suspect the variant was pathogenic despite being synonymous?\",\"answer\":\"The variant is located at the 3′ end of exon 19, a region where changes can affect mRNA splicing. The authors expected that splicing might be disrupted by the nucleotide change.\"},{\"question\":\"How was the splicing effect demonstrated?\",\"answer\":\"RT-PCR using total RNA from the patient’s peripheral blood cells showed skipping of the entire exon 19, resulting in an in-frame deletion. This matched previous in vitro minigene assay observations.\"}]","Cancer Genetics Report - Reclassification of a BRCA2 variant - Case report | PDF",1790096502,13]