Familial cancer with BRCA2 and other germline variants: A case report

IF 1 Q4 GENETICS & HEREDITY Gene Reports Pub Date : 2024-06-11 DOI:10.1016/j.genrep.2024.101945

Shristi Biswas , Swati Manekar , Sonal Bakshi

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Abstract

High-resolution genomic studies can help understanding the predisposition to cancer by identifying constitutional genetic variants of differential penetrance and pathogenicity in a family. We present a case report of whole exome analysis in a case (62/Female) with a history of pancreatic, intestinal, and prostate cancers in the paternal side and her unaffected son from Gujarat, India. Proband showed germline alterations in BRCA2 and NOS3 genes and in NTHL1 gene in her son. BRCA2 c.8954-3C > G has conflicting interpretations being characterized as likely pathogenic and variant of unknown significance (VUS) in 2018 and 2021, while our findings in 2022 classifies it as likely pathogenic. Novel germline genetic variants NOS3 c.1246_1255del (p. Ile417Thrfster9) and NTHL1 c.374dup (p. Val127GlyfsTer43) have been classified as VUS. In-silico analysis of the BRCA2 c.8954-3C > G indicates the location of the genetic variant at the splice site. Proband and her son show co-segregation of 9 constitutional genetic variants; 8 are likely benign and one is benign according to ClinVar. Identification of germline variants and studies on functional evidence will facilitate curated genetic counselling for the family and focussed risk-reduction strategies.

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家族性癌症伴有 BRCA2 和其他种系变异：病例报告

高分辨率基因组研究可以通过识别家族中具有不同渗透性和致病性的宪制性遗传变异来帮助了解癌症的易感性。我们报告了一例来自印度古吉拉特邦的全外显子分析病例（62 岁/女性），该病例的父方及其未受影响的儿子均有胰腺癌、肠癌和前列腺癌病史。Proband显示她儿子的BRCA2和NOS3基因以及NTHL1基因发生了种系改变。BRCA2 c.8954-3C >G在2018年和2021年被定性为可能致病和意义不明变异（VUS），而我们在2022年的研究结果将其归类为可能致病，这两种解释相互矛盾。新的种系遗传变异 NOS3 c.1246_1255del (p. Ile417Thrfster9) 和 NTHL1 c.374dup (p. Val127GlyfsTer43) 被归类为 VUS。对 BRCA2 c.8954-3C > G 的室内分析表明，基因变异位于剪接位点。Proband 和她的儿子显示出 9 个宪制性基因变异的共分离；根据 ClinVar，8 个可能是良性的，1 个是良性的。种系变异的鉴定和功能证据的研究将有助于为该家庭提供有针对性的遗传咨询和降低风险的策略。

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来源期刊

Gene Reports Biochemistry, Genetics and Molecular Biology-Genetics

CiteScore

3.30

自引率

7.70%

发文量

246

审稿时长

49 days

期刊介绍： Gene Reports publishes papers that focus on the regulation, expression, function and evolution of genes in all biological contexts, including all prokaryotic and eukaryotic organisms, as well as viruses. Gene Reports strives to be a very diverse journal and topics in all fields will be considered for publication. Although not limited to the following, some general topics include: DNA Organization, Replication & Evolution -Focus on genomic DNA (chromosomal organization, comparative genomics, DNA replication, DNA repair, mobile DNA, mitochondrial DNA, chloroplast DNA). Expression & Function - Focus on functional RNAs (microRNAs, tRNAs, rRNAs, mRNA splicing, alternative polyadenylation) Regulation - Focus on processes that mediate gene-read out (epigenetics, chromatin, histone code, transcription, translation, protein degradation). Cell Signaling - Focus on mechanisms that control information flow into the nucleus to control gene expression (kinase and phosphatase pathways controlled by extra-cellular ligands, Wnt, Notch, TGFbeta/BMPs, FGFs, IGFs etc.) Profiling of gene expression and genetic variation - Focus on high throughput approaches (e.g., DeepSeq, ChIP-Seq, Affymetrix microarrays, proteomics) that define gene regulatory circuitry, molecular pathways and protein/protein networks. Genetics - Focus on development in model organisms (e.g., mouse, frog, fruit fly, worm), human genetic variation, population genetics, as well as agricultural and veterinary genetics. Molecular Pathology & Regenerative Medicine - Focus on the deregulation of molecular processes in human diseases and mechanisms supporting regeneration of tissues through pluripotent or multipotent stem cells.