bims-lifras Biomed News
on Li-Fraumeni Syndrome
Issue of 2019‒11‒17
thirteen papers selected by
Joanna Zawacka-Pankau



  1. Cancer Res. 2019 Nov 12. pii: canres.0725.2019. [Epub ahead of print]
    Shin SJ, Dodd-Eaton EB, Gao F, Bojadzieva J, Chen J, Kong X, Amos CI, Ning J, Strong LC, Wang W.
      Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disorder associated with TP53 germline mutations and an increased lifetime risk of multiple primary cancers (MPC). Penetrance estimation of time to first and second primary cancer within LFS remains challenging due to limited data and the difficulty of characterizing the effects of a primary cancer on the penetrance of a second primary cancer. Using a recurrent events survival modeling approach that incorporates a family-wise likelihood to efficiently integrate the pedigree structure, we estimated the penetrance for both first and second primary cancer (PC) diagnosis from a pediatric sarcoma cohort at MD Anderson Cancer Center (MDACC, number of families=189; single primary cancer [SPC]=771; MPC=87). Validation of the risk prediction performance was performed using an independent MDACC clinical cohort of TP53 tested individuals (SPC=102; MPC=58). Findings showed that an individual diagnosed at a later age was more likely to be diagnosed with a second PC. Additionally, TP53 mutation carriers had a hazard ratio of 1.65 (95%CI: 1.1, 2.5) for developing a second PC versus SPC. The area under the ROC curve (AUC) for predicting individual outcomes of MPC versus SPC was 0.77. In summary, we provide the first set of penetrance estimates for SPC and MPC for TP53 germline mutation carriers, and demonstrate its accuracy for cancer risk assessment.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-0725
  2. BMC Cancer. 2019 Nov 09. 19(1): 1077
    Soares de Sá BC, de Macedo MP, Torrezan GT, Braga JCT, Fidalgo F, Moredo LF, Lellis R, Duprat JP, Carraro DM.
      BACKGROUND: BRCA1 associated-protein 1 (BAP1) tumor predisposition syndrome is associated with an increased risk for malignant mesotheliomas, uveal and cutaneous melanomas, renal cell carcinomas, and singular cutaneous lesions. The latter are referred to as BAP1-inactivated melanocytic tumors (BIMTs). When multiple BIMTs manifest, they are considered potential markers of germline BAP1 mutations.CASE PRESENTATION: Here, we report a novel pathogenic BAP1 germline variant in a family with a history of BIMTs, cutaneous melanomas, and mesotheliomas. We also describe singular pathological aspects of the patient's BIMT lesions and their correlation with dermoscopic and reflectance confocal microscopy findings.
    CONCLUSIONS: This knowledge is crucial for the recognition of BIMTs by dermatologists and pathologists, allowing the determination of appropriate management for high-risk patients, such as genetic investigations and screening for potentially aggressive tumors.
    Keywords:  BAP1; BIMT; Confocal microscopy; Dermoscopy; Hereditary cancer syndromes
    DOI:  https://doi.org/10.1186/s12885-019-6226-8
  3. Cancer Res. 2019 Nov 12. pii: canres.0728.2019. [Epub ahead of print]
    Shin SJ, Dodd-Eaton EB, Peng G, Bojadzieva J, Chen J, Amos CI, Frone MN, Khincha P, Mai PL, Savage SA, Ballinger ML, Thomas DM, Yuan Y, Strong LC, Wang W.
      Li-Fraumeni syndrome (LFS) is a rare hereditary cancer syndrome associated with an autosomal dominant mutation inheritance in the TP53 tumor suppressor gene and a wide spectrum of cancer diagnoses. The previously developed R package, LFSPRO, is capable of estimating the risk of an individual being a TP53 mutation carrier. However, an accurate estimation of the penetrance of different cancer types in LFS is crucial to improve the clinical characterization and management of high-risk individuals. Here, we developed a competing risk-based statistical model that incorporates the pedigree structure efficiently into the penetrance estimation and corrects for ascertainment bias while also increasing the effective sample size of this rare population. This enabled successful estimation of TP53 penetrance for three LFS cancer types: breast (BR), sarcoma (SA), and others (OT), from 186 pediatric sarcoma families collected at MD Anderson Cancer Center. Penetrance validation was performed on a combined dataset of two clinically ascertained family cohorts with cancer to overcome internal bias in each (total number of families=668). The age-dependent onset probability distributions of specific cancer types were different. For breast cancer, the TP53 penetrance went up at an earlier age than the reported BRCA1/2 penetrance. The prediction performance of the penetrance estimates was validated by the combined independent cohorts (BR=85, SA=540, OT=158). Areas under the ROC curves (AUCs) were 0.92 (BR), 0.75 (SA), and 0.81 (OT). The new penetrance estimates have been incorporated into the current LFSPRO R package in order to provide risk estimates for the diagnosis of breast cancer, sarcoma, or other cancers.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-0728
  4. Neurol Sci. 2019 Nov 14.
    de Almeida Magalhães T, Borges KS, de Sousa GR, Brandalise SR, Seidinger AL, Scrideli CA, Oba-Shinjo SM, Yunes JA, Tone LG.
      BACKGROUND: Ependymoma (EPN) is the third most common childhood cancer of the central nervous system. RELA fusion-positive EPN accounts for approximately 70% of all childhood supratentorial tumors and shows the worst prognosis among the supratentorial EPNs. TP53 mutation is infrequent in RELA fusions EPNs. In the population from the Southern region of Brazil, there is a high incidence of the germline TP53 p.R337H mutation that predisposes carriers to develop early-onset tumors. However, despite this high incidence, the frequency of this mutation among EPN patients remains to be determined. Here, we investigated the presence of the TP53 p.R337H mutation in a larger cohort of pediatric EPNs of three institutions located in the state of São Paulo, Brazil.METHODS: The TP53 p.R337H mutation was screened by conventional RT-PCR and Sanger sequencing in 49 pediatric EPNs diagnosed during the period from 1995 to 2016.
    RESULTS: We described for the first time a case of a 5-year-old girl with RELA fusion EPN with a heterozygous TP53 p.R337H mutation.
    CONCLUSIONS: The present finding indicates that the TP53 p.R337H germline mutation is uncommon in patients with EPN in Brazil and screening of pediatric patients RELA fusion EPN may be informative to better understand the role of TP53 germline mutations in the development and prognosis of these tumors.
    Keywords:  Pediatric ependymoma; RELA fusion; Southern Brazil; TP53 p.R337H mutation
    DOI:  https://doi.org/10.1007/s10072-019-04112-x
  5. PLoS One. 2019 ;14(11): e0221288
    Pouliot GP, Degar J, Hinze L, Kochupurakkal B, Vo CD, Burns MA, Moreau L, Ganesa C, Roderick J, Peirs S, Menten B, Loh ML, Hunger SP, Silverman LB, Harris MH, Stevenson KE, Weinstock DM, Weng AP, Van Vlierberghe P, D'Andrea AD, Gutierrez A.
      BRCA2 (also known as FANCD1) is a core component of the Fanconi pathway and suppresses transformation of immature T-cells in mice. However, the contribution of Fanconi-BRCA pathway deficiency to human T-cell acute lymphoblastic leukemia (T-ALL) remains undefined. We identified point mutations in 9 (23%) of 40 human T-ALL cases analyzed, with variant allele fractions consistent with heterozygous mutations early in tumor evolution. Two of these mutations were present in remission bone marrow specimens, suggesting germline alterations. BRCA2 was the most commonly mutated gene. The identified Fanconi-BRCA mutations encode hypomorphic or null alleles, as evidenced by their inability to fully rescue Fanconi-deficient cells from chromosome breakage, cytotoxicity and/or G2/M arrest upon treatment with DNA cross-linking agents. Disabling the tumor suppressor activity of the Fanconi-BRCA pathway is generally thought to require biallelic gene mutations. However, all mutations identified were monoallelic, and most cases appeared to retain expression of the wild-type allele. Using isogenic T-ALL cells, we found that BRCA2 haploinsufficiency induces selective hypersensitivity to ATR inhibition, in vitro and in vivo. These findings implicate Fanconi-BRCA pathway haploinsufficiency in the molecular pathogenesis of T-ALL, and provide a therapeutic rationale for inhibition of ATR or other druggable effectors of homologous recombination.
    DOI:  https://doi.org/10.1371/journal.pone.0221288
  6. Pathol Oncol Res. 2019 Nov 12.
    Tian P, Cheng X, Zhao Z, Zhang Y, Bao C, Wang Y, Cai S, Ma G, Huang Y.
      Lung cancer is currently a leading cause of cancer-associated mortality worldwide. Despite the increasing evidences of variants that were associated with lung cancer risk, investigations of genetic factors and their roles in genetic susceptibility to lung cancer were limited. Here we systematically investigated the spectrum of pathogenic germline mutations in Chinese population with lung cancer. Genomic profiling of DNA was performed through next-generation sequencing (NGS) on tissue biopsy from 1764 Chinese lung cancer patients with a 381 cancer gene panel between January 01, 2017 and May 07, 2019. Patients with germline mutations were identified, and their clinical information were collected. Of 1764 patients with lung cancer, 67 (3.8%) patients were identified to carry pathogenic or likely pathogenic germline mutations in 25 cancer predisposition genes, with a frequency of 3.6% in lung adenocarcinoma (49/1349), 4.3% in squamous cell lung cancer (14/322), 5.6% in small cell lung cancer (4/72), and none in lung adenosquamous carcinoma (0/21), respectively. The highest pathogenic germline mutational prevalence were found in BRCA2 (0.79%), CHEK2 (0.40%), BRCA1 (0.34%), and TP53 (0.34%). Two splice mutations were reported for the first time in this study. Notably, a majority (85.5%) of the detected germline mutations fell in DNA damage repair pathways.
    Keywords:  DNA damage repair pathway; Germline mutation; Lung cancer; Next-generation sequencing
    DOI:  https://doi.org/10.1007/s12253-019-00771-5
  7. Clin J Oncol Nurs. 2019 Dec 01. 23(6): 579-582
    King E, Nehoray BM.
      Hereditary pancreatic cancer continues to pose challenges to providers, as well as to patients and their families. Pancreatic cancer has a poor prognosis, and individuals with family histories of pancreatic cancer are often motivated to pursue genetic testing. This article reviews various hereditary pancreatic cancer syndromes, as well as pancreatic cancer screening recommendations, options, and limitations.
    Keywords:  gene mutation; genetic testing; hereditary pancreatic cancer; risk assessment
    DOI:  https://doi.org/10.1188/19.CJON.579-582
  8. J Genet Couns. 2019 Nov 14.
    Dekanek EW, Thull DL, Massart M, Grubs RE, Rajkovic A, Mai PL.
      BRCA1 and BRCA2 (BRCA1/2) testing is standard for individuals with personal and/or family history suggestive of hereditary breast and ovarian cancer syndrome. The indications for testing have been expanding. To accommodate the need, incorporation of cancer genetic services into the practice of non-genetic healthcare providers should be considered. We carried out a survey to evaluate the knowledge and opinions regarding BRCA1/2 testing among primary care providers. The survey was sent to 245 Obstetrics/Gynecology and 97 Family Medicine physicians in the UPMC network. Eighty-six completed the survey between July 2015 and September 2015. The average correct responses to knowledge questions was 73%. A few respondents reported being completely confident, and ~50% reported being somewhat confident, in providing BRCA1/2-related information. Respondents selected genetic specialists and oncologists as the most qualified to provide cancer genetic services. Several perceived barriers and motivating factors to the implementation of BRCA1/2 testing in primary care were identified. The findings from this study suggested that primary care providers were not uniformly ready to provide BRCA1/2 genetic testing. Availability of professional society guidelines and evidence of testing's usefulness might motivate the incorporation of BRCA1/2 genetic testing into primary care practices. These findings would help guide future educational efforts to promote provision of cancer genetic services by non-genetic professionals.
    Keywords:   BRCA ; cancer genetics; education; genetic counseling; genetic knowledge; genetic services; primary care providers
    DOI:  https://doi.org/10.1002/jgc4.1189
  9. Int J Hematol. 2019 Nov 11.
    Polprasert C, Takeda J, Niparuck P, Rattanathammethee T, Pirunsarn A, Suksusut A, Kobbuaklee S, Wudhikarn K, Lawasut P, Kongkiatkamon S, Chuncharunee S, Songserm K, Phowthongkum P, Bunworasate U, Nannya Y, Yoshida K, Makishima H, Ogawa S, Rojnuckarin P.
      Germline DDX41 mutations were recently reported to cause MDS/AML and donor-derived leukemia after transplantation. While previously described in Western countries, DDX41 variants have not been reported in a Southeast Asian population. We performed targeted sequencing of blood or bone marrow samples from 109 Thai patients with myeloid malignancies. Among the 109 patients (75 MDS, 8 MPN, 11 MDS/MPN and 15 AML), the most frequent mutations were in ASXL1 (17.4%), TET2 (16.5%) and SRSF2 (12.8%), respectively. DDX41 variants were detectable in six (5.5%) cases. Four patients exhibited three presumable germline DDX41 mutations: p.S21fs (n = 2), p.F235fs (n = 1), and p.R339H (n = 1). While p.S21fs was previously reported in myeloid neoplasm, the latter two variants have not been described. Two of these cases harbored concomitant probable germline/somatic DDX41 mutations (p.S21fs/p.R525H and p.R339H/p.K494T), while the other two patients carried only somatic mutations (p.R525H and p.F438L). The p.K494T and p.F438L variants have not been previously reported. In patients with DDX41 alterations, the diagnoses were MDS with excess blasts (4), secondary AML (1) and low-risk MDS (1). In conclusion, we identified DDX41 variants in Thai patients with myeloid malignancies in which these variants could be used to assess predisposition to MDS in Southeast Asia.
    Keywords:  Acute myeloid leukemia; DDX41 alterations; Familial MDS/AML; Myelodysplastic syndromes; Southeast asia
    DOI:  https://doi.org/10.1007/s12185-019-02770-3
  10. Cancer Genet. 2019 Oct 16. pii: S2210-7762(19)30335-7. [Epub ahead of print]240 23-32
    Cecener G, Takanlou LS, Takanlou MS, Egeli U, Eskiler GG, Aksoy S, Unal U, Tezcan H, Eryilmaz IE, Gokgoz MS, Tunca B, Cubukcu E, Evrensel T, Cetintas S, Tasdelen I.
      The aim of this study was to identify the frequency and spectrum of germline BRCA1/2 pathogenic alterations in a cohort of patients with breast carcinoma. In this study, a total of 603 breast cancer subjects from Turkey were screened for BRCA1/BRCA2 mutations using HDA and Sanger sequencing. In the present study, 21 BRCA1 and BRCA2 pathogenic variants were detected in 30 patients and BRCA1/2 mutations were significantly associated with a family history of breast/ovarian cancer. Analysis of overall survival for BRCA1/BRCA2 mutation carriers showed a trend for poor overall survival only in BRCA1 carriers, although this was not statistically significant in BRCA1 and BRCA2 mutation carriers. The c.5266dupC mutation is one of the most frequently reported mutations in BRCA1 and was identified in five breast cancer patients in our study. The most common BRCA2 gene mutations in the present study were c.8940delA and c.9097dupA, which were found in seven patients. We found mostly BRCA1 and BRCA2 mutation carriers in those patients who showed hormone-positive features. In conclusion, our data showed differences in the distribution of the mutation spectrum of BRCA1 and BRCA2 in Turkey.
    Keywords:  BRCA1; BRCA2; Breast cancer; Pathogenic mutations; Variant of uncertain significance
    DOI:  https://doi.org/10.1016/j.cancergen.2019.10.004
  11. J Med Genet. 2019 Nov 12. pii: jmedgenet-2019-106407. [Epub ahead of print]
    Bancroft EK, Saya S, Brown E, Thomas S, Taylor N, Rothwell J, Pope J, Chamberlain A, Page E, Benafif S, Hanson H, Dias A, Mikropoulos C, Izatt L, Side L, Walker L, Donaldson A, Cook JA, Barwell J, Wiles V, Limb L, Eccles DM, Leach MO, Shanley S, Gilbert FJ, Gallagher D, Rajashanker B, Whitehouse RW, Koh DM, Sohaib SA, Evans DG, Eeles RA, Walker LG.
      BACKGROUND: Germline TP53 gene pathogenic variants (pv) cause a very high lifetime risk of developing cancer, almost 100% for women and 75% for men. In the UK, annual MRI breast screening is recommended for female TP53 pv carriers. The SIGNIFY study (Magnetic Resonance Imaging screening in Li Fraumeni syndrome: An exploratory whole body MRI) study reported outcomes of whole-body MRI (WB-MRI) in a cohort of 44 TP53 pv carriers and 44 matched population controls. The results supported the use of a baseline WB-MRI screen in all adult TP53 pv carriers. Here we report the acceptability of WB-MRI screening and effects on psychosocial functioning and health-related quality of life in the short and medium terms.METHODS: Psychosocial and other assessments were carried out at study enrolment, immediately before MRI, before and after MRI results, and at 12, 26 and 52 weeks' follow-up.
    RESULTS: WB-MRI was found to be acceptable with high levels of satisfaction and low levels of psychological morbidity throughout. Although their mean levels of cancer worry were not high, carriers had significantly more cancer worry at most time-points than controls. They also reported significantly more clinically significant intrusive and avoidant thoughts about cancer than controls at all time-points. There were no clinically significant adverse psychosocial outcomes in either carriers with a history of cancer or in those requiring further investigations.
    CONCLUSION: WB-MRI screening can be implemented in TP53 pv carriers without adverse psychosocial outcomes in the short and medium terms. A previous cancer diagnosis may predict a better psychosocial outcome. Some carriers seriously underestimate their risk of cancer. Carriers of pv should have access to a clinician to help them develop adaptive strategies to cope with cancer-related concerns and respond to clinically significant depression and/or anxiety.
    Keywords:  Li-Fraumeni syndrome; MRI; TP53 gene pathogenic variant; case controlled study; psychosocial
    DOI:  https://doi.org/10.1136/jmedgenet-2019-106407
  12. Cancer Res. 2019 Nov 13. pii: canres.1840.2019. [Epub ahead of print]
    Patel VL, Busch EL, Friebel TM, Cronin A, Leslie G, McGuffog L, Adlard J, Agata S, Agnarsson BA, Ahmed M, Aittomäki K, Alducci E, Andrulis IL, Arason A, Arnold N, Artioli G, Arver B, Auber B, Azzollini J, Balmaña J, Barkardottir RB, Barnes DR, Barroso A, Barrowdale D, Belotti M, Benitez J, Bertelsen B, Blok MJ, Bodrogi I, Bonadona V, Bonanni B, Bondavalli D, Boonen SE, Borde J, Borg A, Bradbury AR, Brady A, Brewer C, Brunet J, Buecher B, Buys SS, Cabezas-Camarero S, Caldés T, Caliebe A, Caligo MA, Calvello M, Campbell IG, Carnevali I, Carrasco E, Chan TL, Chu ATW, Chung WK, Claes KBM, Collaborators GS, Collaborators E, Cook J, Cortesi L, Couch FJ, Daly MB, Damante G, Darder E, Davidson R, de la Hoya M, Della Puppa L, Dennis J, Díez O, Ding YC, Ditsch N, Domchek SM, Donaldson A, Dworniczak B, Easton DF, Eccles DM, Eeles RA, Ehrencrona H, Ejlertsen B, Engel C, Evans DG, Faivre L, Faust U, Feliubadaló L, Foretova L, Fostira F, Fountzilas G, Frost D, García-Barberán V, Garre P, Gauthier-Villars M, Géczi L, Gehrig A, Gerdes AM, Gesta P, Giannini G, Glendon G, Godwin AK, Goldgar DE, Greene MH, Gutierrez-Barrera AM, Hahnen E, Hamann U, Hauke J, Herold N, Hogervorst FBL, Honisch E, Hopper JL, Hulick PJ, Investigators K, Investigators H, Izatt L, Jager A, James P, Janavicius R, Jensen UB, Jensen TD, Johannsson OT, John EM, Joseph V, Kang E, Kast K, Kiiski JI, Kim SW, Kim Z, Ko KP, Konstantopoulou I, Kramer G, Krogh L, Kruse TA, Kwong A, Larsen M, Lasset C, Lautrup C, Lázaro C, Lee J, Lee JW, Lee MH, Lemke J, Lesueur F, Liljegren A, Lindblom A, Llovet P, Lopez-Fernández A, Lopez-Perolio I, Lorca V, Loud JT, Ma ESK, Mai PL, Manoukian S, Mari V, Martin L, Matricardi L, Mebirouk N, Medici V, Meijers-Heijboer HEJ, Meindl A, Mensenkamp AR, Miller C, Molina Gomes D, Montagna M, Mooij TM, Moserle L, Mouret-Fourme E, Mulligan AM, Nathanson KL, Navratilova M, Nevanlinna H, Niederacher D, Cilius Nielsen FC, Nikitina-Zake L, Offit K, Olah E, Olopade OI, Ong KR, Osorio A, Ott CE, Palli D, Park SK, Parsons MT, Pedersen IS, Peissel B, Peixoto A, Pérez-Segura P, Peterlongo P, Høgh Petersen A, Porteous ME, Pujana MA, Radice P, Ramser J, Rantala J, Rashid MU, Rhiem K, Rizzolo P, Robson ME, Rookus MA, Rossing CM, Ruddy KJ, Santos C, Saule C, Scarpitta R, Schmutzler RK, Schuster H, Senter L, Seynaeve CM, Shah PD, Sharma P, Shin VY, Silvestri V, Simard J, Singer CF, Skytte AB, Snape K, Solano AR, Soucy P, Southey MC, Spurdle AB, Steele L, Steinemann D, Stoppa-Lyonnet D, Stradella A, Sunde L, Sutter C, Tan YY, Teixeira MR, Teo SH, Thomassen M, Tibiletti MG, Tischkowitz M, Tognazzo S, Toland AE, Tommasi S, Torres D, Toss A, Trainer AH, Tung N, van Asperen CJ, van der Baan FH, van der Kolk LE, van der Luijt RB, van Hest LP, Varesco L, Varon-Mateeva R, Viel A, Vierstraete J, Villa R, von Wachenfeldt A, Wagner P, Wang-Gohrke S, Wappenschmidt B, Weitzel JN, Wieme G, Yadav S, Yannoukakos D, Yoon SY, Zanzottera C, Zorn KK, D'Amico AV, Freedman ML, Pomerantz MM, Chenevix-Trench G, Antoniou AC, Neuhausen SL, Ottini L, Nielsen HR, Rebbeck TR.
      Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer (PCa). We evaluated whether PSVs in BRCA1/2 were associated with risk of overall PCa or high grade (Gleason 8+) PCa using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with PCa, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without PCa. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of PCa compared with reference bin c.1001-c.7913 (HR=1.78, 95%CI: 1.25-2.52, p=0.001), as well as elevated risk of Gleason 8+ PCa (HR=3.11, 95%CI: 1.63-5.95, p=0.001). c.756-c.1000 was also associated with elevated PCa risk (HR=2.83, 95%CI: 1.71-4.68, p=0.00004) and elevated risk of Gleason 8+ PCa (HR=4.95, 95%CI: 2.12-11.54, p=0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive PCa.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-1840
  13. Mol Genet Genomic Med. 2019 Nov 13. e1045
    van Luttikhuizen JL, Bublitz J, Schubert S, Schmidt G, Hofmann W, Morlot S, Buurman R, Auber B, Schlegelberger B, Steinemann D.
      BACKGROUND: Germline mutations in BRCA1/2 significantly contribute to hereditary breast and/or ovarian cancer. Here, we report a novel BRCA2 duplication of exons 22-24 in a female patient with bilateral breast cancer at age 35 and 44. The duplicated region was initially detected by gene panel sequencing and multiplex ligation-dependent probe amplification. However, the location and orientation of the duplicated region was unknown. Therefore, it was initially classified as a variant of unknown significance.METHODS: The spatial directional characterization of the BRCA2 duplication was achieved by targeted enrichment of the whole-genomic BRCA2 locus including exons and introns, and subsequent high-throughput sequencing. Subsequently, bioinformatics tools and a breakpoint-spanning PCR were used for identification of location and orientation of the duplication.
    RESULTS: The duplicated region was arranged in tandem and direct orientation (Chr13(GRCh37):g.32951579_32960394dup; NM_000059.3 c.8754 + 651_9256+6112dup p.(Ala3088Phefs*3)). It is predicted to result in a frameshift and a premature stop codon likely triggering nonsense-mediated mRNA decay. Consequently, it is regarded as pathogenic.
    CONCLUSION: This case study demonstrates that a comprehensive characterization of a structural variant by breakpoint assessment is crucial for its correct classification. Therefore, sequencing strategies including non-coding regions might be necessary to identify cancer predispositions in affected families.
    Keywords:  BRCA2; copy number variation; hereditary breast and/or ovarian cancer; high-throughput sequencing; large genomic rearrangement
    DOI:  https://doi.org/10.1002/mgg3.1045