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Case Report| Volume 256, P127-130, August 2021

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A hereditary ovarian cancer family with rare pathogenic splicing mutation: Implications for variant interpretation

  • Author Footnotes
    1 These authors contributed equally to this work.
    Ke Wang
    Correspondence
    Corresponding authors.
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Gynecological Oncology Department, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin, P R China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Yingnan Ye
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Cancer Molecular Diagnostics Core, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer Tianjin Medical University Cancer Institute & Hospital, Tianjin, P R China
    Search for articles by this author
  • Lewen Bao
    Affiliations
    Gynecological Oncology Department, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin, P R China
    Search for articles by this author
  • Yanan Cheng
    Affiliations
    Cancer Molecular Diagnostics Core, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer Tianjin Medical University Cancer Institute & Hospital, Tianjin, P R China
    Search for articles by this author
  • Yandong Cao
    Affiliations
    Analyses Technology Co. Ltd., Beijing, P R China
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  • Jinpu Yu
    Correspondence
    Corresponding authors.
    Affiliations
    Cancer Molecular Diagnostics Core, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer Tianjin Medical University Cancer Institute & Hospital, Tianjin, P R China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.
Published:May 25, 2021DOI:https://doi.org/10.1016/j.cancergen.2021.05.007
A hereditary ovarian cancer family with rare pathogenic splicing mutation: Implications for variant interpretation
Previous ArticleLong-read nanopore sequencing enables accurate confirmation of a recurrent PMS2 insertion–deletion variant located in a region of complex genomic architecture
Next ArticleEML4-ALK fusion variant.3 and co-occurrent PIK3CA E542K mutation exhibiting primary resistance to three generations of ALK inhibitors

      Highlights

      • •
        Rare pathogenic splicing mutation in BRCA1 gene.
      • •
        A rare pathogenic splicing mutation found in FHOCs family.

      Abstract

      The BRCA1/2 gene is important for assessing the risk of familial/hereditary ovarian cancer (OC). This case is a patient with OC, and two of her immediate family members are cancer patients. We sequenced the coding and splicing regions of 42 OC susceptibility genes, and found a rare pathogenic splicing mutation BRCA1:c.132C > T (p.cys44 =) in 2 patients. Although the mutation is synonymous, software prediction and functional verification have shown that it affects alternative splicing and leads to frameshift mutations (c.131_134del). Chromosome microarray analysis of the tissue samples revealed the presence of a BRCA1 gene deletion with a fragment size of 1.42 Mb and an HRD score of 71. In addition, the proband showed a sensitive response to platinum treatment. This case suggests the clinical significance of OC susceptibility genes sequencing and HRD scoring in screening hereditary OC families.

      Keywords

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      Reference

        • Torre L.A.
        • Bray F.
        • Siegel R.L.
        • Ferlay J.
        • Lortet-Tieulent J.
        • Jemal A.
        Global cancer statistics, 2012.
        CA Cancer J Clin. 2015; 65: 87-108
        View in Article
        • Siegel R.L.
        • Miller K.D.
        • Jemal A.
        Cancer statistics, 2017.
        CA Cancer J Clin. 2017; 67: 7-30
        View in Article
        • Ledermann J.A.
        • Harter P.
        • Gourley C.
        • Friedlander M.
        • Vergote I.
        • Rustin G.
        • Scott C.
        • Meier W.
        • Shapira-Frommer R.
        • Safra T.
        • Matei D.
        • Fielding A.
        • Spencer S.
        • Rowe P.
        • Lowe E.
        • Hodgson D.
        • Sovak M.A.
        • Matulonis U.
        Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial.
        Lancet Oncol. 2016; 17: 1579-1589
        View in Article
        • Graybill W.S.
        • Pothuri B.
        • Chase D.M.
        • Monk B.J.
        Poly(ADP-ribose) polymerase (PARP) inhibitors as treatment versus maintenance in ovarian carcinoma.
        Gynecol Oncol. 2017; 146: 11-15
        View in Article
        • Ledermann J.A.
        • Drew Y.
        • Kristeleit R.S.
        Homologous recombination deficiency and ovarian cancer.
        Eur J Cancer. 2016; 60: 49-58
        View in Article
        • Walsh T.
        • Casadei S.
        • Lee M.K.
        • Pennil C.C.
        • Nord A.S.
        • Thornton A.M.
        • Roeb W.
        • Agnew K.J.
        • Stray S.M.
        • Wickramanayake A.
        • Norquist B.
        • Pennington K.P.
        • Garcia R.L.
        • King M.C.
        • Swisher E.M.
        Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing.
        Proc Natl Acad Sci USA. 2011; 108: 18032-18037
        View in Article
        • Hall M.J.
        • Obeid E.I.
        • Schwartz S.C.
        • Mantia-Smaldone G.
        • Forman A.D.
        • Daly M.B.
        Genetic testing for hereditary cancer predisposition: BRCA1/2, Lynch syndrome, and beyond.
        Gynecol Oncol. 2016; 140: 565-574
        View in Article
        • Steffensen A.Y.
        • Dandanell M.
        • Jonson L.
        • Ejlertsen B.
        • Gerdes A.M.
        • Nielsen F.C.
        • Hansen T.
        Functional characterization of BRCA1 gene variants by mini-gene splicing assay.
        Eur J Hum Genet EJHG. 2014; 22: 1362-1368
        View in Article
        • Rebbeck T.R.
        • Friebel T.M.
        • Friedman E.
        • Hamann U.
        • Huo D.
        • Kwong A.
        • Olah E.
        • Olopade O.I.
        • Solano A.R.
        • Teo S.H.
        • Thomassen M.
        • Weitzel J.N.
        • Chan T.L.
        • Couch F.J.
        • Goldgar D.E.
        • Kruse T.A.
        • Palmero E.I.
        • Park S.K.
        • Torres D.
        • van Rensburg E.J.
        • McGuffog L.
        • Parsons M.T.
        • Leslie G.
        • Aalfs C.M.
        • Abugattas J.
        • Adlard J.
        • Agata S.
        • Aittomaki K.
        • Andrews L.
        • Andrulis I.L.
        • Arason A.
        • Arnold N.
        • Arun B.K.
        • Asseryanis E.
        • Auerbach L.
        • Azzollini J.
        • Balmana J.
        • Barile M.
        • Barkardottir R.B.
        • Barrowdale D.
        • Benitez J.
        • Berger A.
        • Berger R.
        • Blanco A.M.
        • Blazer K.R.
        • Blok M.J.
        • Bonadona V.
        • Bonanni B.
        • Bradbury A.R.
        • Brewer C.
        • Buecher B.
        • Buys S.S.
        • Caldes T.
        • Caliebe A.
        • Caligo M.A.
        • Campbell I.
        • Caputo S.M.
        • Chiquette J.
        • Chung W.K.
        • Claes K.B.M.
        • Collee J.M.
        • Cook J.
        • Davidson R.
        • de la Hoya M.
        • De Leeneer K.
        • de Pauw A.
        • Delnatte C.
        • Diez O.
        • Ding Y.C.
        • Ditsch N.
        • Domchek S.M.
        • Dorfling C.M.
        • Velazquez C.
        • Dworniczak B.
        • Eason J.
        • Easton D.F.
        • Eeles R.
        • Ehrencrona H.
        • Ejlertsen B.
        • Embrace
        • Engel C.
        • Engert S.
        • Evans D.G.
        • Faivre L.
        • Feliubadalo L.
        • Ferrer S.F.
        • Foretova L.
        • Fowler J.
        • Frost D.
        • Galvao H.C.R.
        • Ganz P.A.
        • Garber J.
        • Gauthier-Villars M.
        • Gehrig A.
        • Gerdes A.M.
        • Gesta P.
        • Giannini G.
        • Giraud S.
        • Glendon G.
        • Godwin A.K.
        • Greene M.H.
        • Gronwald J.
        • Gutierrez-Barrera A.
        • Hahnen E.
        • Hauke J.
        • Hebon
        • Henderson A.
        • Hentschel J.
        • Hogervorst F.B.L.
        • Honisch E.
        • Imyanitov E.N.
        • Isaacs C.
        • Izatt L.
        • Izquierdo A.
        • Jakubowska A.
        • James P.
        • Janavicius R.
        • Jensen U.B.
        • John E.M.
        • Vijai J.
        • Kaczmarek K.
        • Karlan B.Y.
        • Kast K.
        • Investigators K.
        • Kim S.W.
        • Konstantopoulou I.
        • Korach J.
        • Laitman Y.
        • Lasa A.
        • Lasset C.
        • Lazaro C.
        • Lee A.
        • Lee M.H.
        • Lester J.
        • Lesueur F.
        • Liljegren A.
        • Lindor N.M.
        • Longy M.
        • Loud J.T.
        • Lu K.H.
        • Lubinski J.
        • Machackova E.
        • Manoukian S.
        • Mari V.
        • Martinez-Bouzas C.
        • Matrai Z.
        • Mebirouk N.
        • Meijers-Heijboer H.E.J.
        • Meindl A.
        • Mensenkamp A.R.
        • Mickys U.
        • Miller A.
        • Montagna M.
        • Moysich K.B.
        • Mulligan A.M.
        • Musinsky J.
        • Neuhausen S.L.
        • Nevanlinna H.
        • Ngeow J.
        • Nguyen H.P.
        • Niederacher D.
        • Nielsen H.R.
        • Nielsen F.C.
        • Nussbaum R.L.
        • Offit K.
        • Ofverholm A.
        • Ong K.R.
        • Osorio A.
        • Papi L.
        • Papp J.
        • Pasini B.
        • Pedersen I.S.
        • Peixoto A.
        • Peruga N.
        • Peterlongo P.
        • Pohl E.
        • Pradhan N.
        • Prajzendanc K.
        • Prieur F.
        • Pujol P.
        • Radice P.
        • Ramus S.J.
        • Rantala J.
        • Rashid M.U.
        • Rhiem K.
        • Robson M.
        • Rodriguez G.C.
        • Rogers M.T.
        • Rudaitis V.
        • Schmidt A.Y.
        • Schmutzler R.K.
        • Senter L.
        • Shah P.D.
        • Sharma P.
        • Side L.E.
        • Simard J.
        • Singer C.F.
        • Skytte A.B.
        • Slavin T.P.
        • Snape K.
        • Sobol H.
        • Southey M.
        • Steele L.
        • Steinemann D.
        • Sukiennicki G.
        • Sutter C.
        • Szabo C.I.
        • Tan Y.Y.
        • Teixeira M.R.
        • Terry M.B.
        • Teule A.
        • Thomas A.
        • Thull D.L.
        • Tischkowitz M.
        • Tognazzo S.
        • Toland A.E.
        • Topka S.
        • Trainer A.H.
        • Tung N.
        • van Asperen C.J.
        • van der Hout A.H.
        • van der Kolk L.E.
        • van der Luijt R.B.
        • Van Heetvelde M.
        • Varesco L.
        • Varon-Mateeva R.
        • Vega A.
        • Villarreal-Garza C.
        • von Wachenfeldt A.
        • Walker L.
        • Wang-Gohrke S.
        • Wappenschmidt B.
        • Weber B.H.F.
        • Yannoukakos D.
        • Yoon S.Y.
        • Zanzottera C.
        • Zidan J.
        • Zorn K.K.
        • Hutten Selkirk C.G.
        • Hulick P.J.
        • Chenevix-Trench G.
        • Spurdle A.B.
        • Antoniou A.C.
        • Nathanson K.L
        • Collaborators G.S.
        Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.
        Hum Mutat. 2018; 39: 593-620
        View in Article
        • Chao A.
        • Lai C.H.
        • Wang T.H.
        • Jung S.M.
        • Lee Y.S.
        • Chang W.Y.
        • Yang L.Y.
        • Ku F.C.
        • Huang H.J.
        • Chao A.S.
        • Wang C.J.
        • Chang T.C.
        • Wu R.C.
        Genomic scar signatures associated with homologous recombination deficiency predict adverse clinical outcomes in patients with ovarian clear cell carcinoma.
        J Mol Med. 2018; 96: 527-536
        View in Article
        • Watkins J.A.
        • Irshad S.
        • Grigoriadis A.
        • Tutt A.N.
        Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers.
        Breast Cancer Res BCR. 2014; 16: 211
        View in Article
        • Alsop K.
        • Fereday S.
        • Meldrum C.
        • deFazio A.
        • Emmanuel C.
        • George J.
        • Dobrovic A.
        • Birrer M.J.
        • Webb P.M.
        • Stewart C.
        • Friedlander M.
        • Fox S.
        • Bowtell D.
        • Mitchell G.
        BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian ovarian cancer study group.
        J Clin Oncol Off J Am Soc Clin Oncol. 2012; 30: 2654-2663
        View in Article
        • Toss A.
        • Tomasello C.
        • Razzaboni E.
        • Contu G.
        • Grandi G.
        • Cagnacci A.
        • Schilder R.J.
        • Cortesi L.
        Hereditary ovarian cancer: not only BRCA 1 and 2 genes.
        Biomed Res Int. 2015; 2015341723
        View in Article
        • Chen S.
        • Parmigiani G.
        Meta-analysis of BRCA1 and BRCA2 penetrance.
        J Clin Oncol Off J Am Soc Clin Oncol. 2007; 25: 1329-1333
        View in Article

      Article info

      Publication history

      Published online: May 25, 2021
      Accepted: May 20, 2021
      Received in revised form: May 8, 2021
      Received: January 15, 2021

      Identification

      DOI: https://doi.org/10.1016/j.cancergen.2021.05.007

      Copyright

      © 2021 Elsevier Inc. All rights reserved.

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