Re‐evaluating the pathogenicity of the c.783+2T>C BAP1 germline variant

2021 ◽  
Vol 42 (5) ◽  
pp. 592-599
Author(s):  
Yael Goldberg ◽  
Yael Laitman ◽  
Merav Ben David ◽  
Lily Bazak ◽  
Gabriel Lidzbarsky ◽  
...  
Keyword(s):  
Germline Variant

APC germline variant analysis in the adenomatous polyposis phenotype in Japanese patients

2021 ◽  
Author(s):  
Misato Takao ◽  
Tatsuro Yamaguchi ◽  
Hidetaka Eguchi ◽  
Takeshi Yamada ◽  
Yasushi Okazaki ◽  
...  
Keyword(s):  
Japanese Patients ◽  
Adenomatous Polyposis ◽  
Germline Variant ◽  
Variant Analysis

scholarly journals Accuracy and efficiency of germline variant calling pipelines for human genome data

2020 ◽  
Author(s):  
Sen Zhao ◽  
Oleg Agafonov ◽  
Abdulrahman Azab ◽  
Tomasz Stokowy ◽  
Eivind Hovig
Keyword(s):  
Large Scale ◽  
Variant Calling ◽  
Performance Comparison ◽  
Next Generation Sequencing Technology ◽  
Genome Data ◽  
Germline Variant ◽  
Causal Variants ◽  
Variant Detection ◽  
Variant Analysis ◽  
Human Genome Data

AbstractAdvances in next-generation sequencing technology has enabled whole genome sequencing (WGS) to be widely used for identification of causal variants in a spectrum of genetic-related disorders, and provided new insight into how genetic polymorphisms affect disease phenotypes. The development of different bioinformatics pipelines has continuously improved the variant analysis of WGS data, however there is a necessity for a systematic performance comparison of these pipelines to provide guidance on the application of WGS-based scientific and clinical genomics. In this study, we evaluated the performance of three variant calling pipelines (GATK, DRAGEN™ and DeepVariant) using Genome in a Bottle Consortium, “synthetic-diploid” and simulated WGS datasets. DRAGEN™ and DeepVariant show a better accuracy in SNPs and indels calling, with no significant differences in their F1-score. DRAGEN™ platform offers accuracy, flexibility and a highly-efficient running speed, and therefore superior advantage in the analysis of WGS data on a large scale. The combination of DRAGEN™ and DeepVariant also provides a good balance of accuracy and efficiency as an alternative solution for germline variant detection in further applications. Our results facilitate the standardization of benchmarking analysis of bioinformatics pipelines for reliable variant detection, which is critical in genetics-based medical research and clinical application.

Performance Comparison of Computational Prediction Methods for the Function and Pathogenicity of Non-coding Variants

2021 ◽  
Author(s):  
Zheng Wang ◽  
Guihu Zhao ◽  
Bin Li ◽  
Zhenghuan Fang ◽  
Qian Chen ◽  
...  
Keyword(s):  
Computational Methods ◽  
Method Development ◽  
De Novo ◽  
Autism Spectrum ◽  
Common Variant ◽  
Tool Selection ◽  
Somatic Variant ◽  
Germline Variant ◽  
Regulatory Variant ◽  
Coding Variants

Non-coding variants in the human genome greatly influence some traits and complex diseases by their own regulation and modification effects. Hence, an increasing number of computational methods are developed to predict the effects of variants in the human non-coding sequences. However, it is difficult for users with insufficient knowledge about the performances of computational methods to select appropriate computational methods from dozens of methods. In order to solve this problem, we assessed 12 performance measures of 24 methods on four independent non-coding variant benchmark datasets: (Ⅰ) rare germline variant from ClinVar, (Ⅱ) rare somatic variant from COSMIC, (Ⅲ) common regulatory variant dataset, and (Ⅳ) disease associated common variant dataset. All 24 tested methods performed differently under various conditions, indicating that these methods have varying strengths and weaknesses under different scenarios. Importantly, the performance of existing methods was acceptable in the rare germline variant from ClinVar with area under curves (AUCs) of 0.4481 - 0.8033 and poor in the rare somatic variant from COSMIC (AUCs: 0.4984 - 0.7131), common regulatory variant dataset (AUCs: 0.4837 - 0.6472), and disease associated common variant dataset (AUCs: 0.4766 -0.5188). We also compared the prediction performance among 24 methods for non-coding de novo mutations in autism spectrum disorder and found that the CADD and CDTS methods showed better performance. Summarily, we assessed the performances of 24 computational methods under diverse scenarios, providing preliminary advice for proper tool selection and new method development in interpreting non-coding variants.

Genomic profiling of multiple primary cancers including synchronous lung adenocarcinoma and bilateral malignant mesotheliomas: Identification of a novel BAP1 germline variant

2020 ◽  
Vol 70 (10) ◽  
pp. 775-780
Author(s):  
Aya Shinozaki‐Ushiku ◽  
Shinji Kohsaka ◽  
Hidenori Kage ◽  
Katsutoshi Oda ◽  
Kiyoshi Miyagawa ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Multiple Primary Cancers ◽  
Genomic Profiling ◽  
Germline Variant ◽  
Multiple Primary

scholarly journals Are Pathogenic Germline Variants in Metastatic Melanoma Associated with Resistance to Combined Immunotherapy?

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1101 ◽  
Author(s):  
Teresa Amaral ◽  
Martin Schulze ◽  
Tobias Sinnberg ◽  
Maike Nieser ◽  
Peter Martus ◽  
...  
Keyword(s):  
Dna Repair ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Advanced Melanoma ◽  
Germline Variants ◽  
Cox Regression Analysis ◽  
Dna Repair Mechanisms ◽  
Germline Variant ◽  
Repair Mechanisms ◽  
Combined Immunotherapy

Background: Combined immunotherapy has significantly improved survival of patients with advanced melanoma, but there are still patients that do not benefit from it. Early biomarkers that indicate potential resistance would be highly relevant for these patients. Methods: We comprehensively analyzed tumor and blood samples from patients with advanced melanoma, treated with combined immunotherapy and performed descriptive and survival analysis. Results: Fifty-nine patients with a median follow-up of 13 months (inter quartile range (IQR) 11–15) were included. Interestingly, nine patients were found to have pathogenic or likely pathogenic (P/LP) germline variants in one of these genes: BRCA2, POLE, WRN, FANCI, CDKN2A, BAP1, PALB2 and RAD54B. Most of them are involved in DNA repair mechanisms. Patients with P/LP germline variants had a significantly shorter progression-free survival (PFS) and melanoma specific survival (MSS) compared to patients without P/LP germline variants (HR = 2.16; 95% CI: 1.01–4.64; p = 0.048 and HR = 3.21; 95% CI: 1.31–7.87; p = 0.011, respectively). None of the patients with a P/LP germline variant responded to combined immunotherapy. In the multivariate Cox-regression analysis, presence of a P/LP germline variant, S100B and lactate dehydrogenase (LDH) remained independently significant factors for MSS (p = 0.036; p = 0.044 and p = 0.001, respectively). Conclusions: The presence of P/LP germline variants was associated with resistance to combined immunotherapy in our cohort. As genes involved in DNA repair mechanisms are also involved in lymphocyte development and T-cell differentiation, a P/LP germline variant in these genes may preclude an antitumor immune response.

scholarly journals A novel germline BMPR1A variant (c.72_73delGA) in a Japanese family with hereditary mixed polyposis syndrome

2020 ◽  
Vol 50 (7) ◽  
pp. 826-829
Author(s):  
Yosuke Miyahara ◽  
Hideyuki Ishida ◽  
Koichi Kawabe ◽  
Hiroyuki Eto ◽  
Toyotaka Kasai ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Autosomal Dominant ◽  
Hyperplastic Polyps ◽  
Autosomal Dominant Disorder ◽  
Polyposis Syndrome ◽  
Japanese Family ◽  
Germline Variant ◽  
Juvenile Polyps ◽  
Increased Risk ◽  
Cancer Syndromes

Abstract Hereditary mixed polyposis syndrome (HMPS) is a rare autosomal dominant disorder characterized by a mixture of typical and/or atypical juvenile polyps, adenomas and hyperplastic polyps, resulting in an increased risk of colorectal cancer. In HMPS, four different germline BMPR1A variants from five unrelated families have been reported. This study is the first to report HMPS within a Japanese family. The proband underwent repeated colonoscopic polypectomies over a 5-year period, since the age of 67. Histological examination of these resected polyps revealed adenomas, juvenile-like polyps and hyperplastic changes. Genetic testing was conducted to identify the causative genes for hereditary gastrointestinal cancer syndromes, including BMPR1A. We detected a germline variant, c.72_73delGA, in BMPR1A. The proband’s elder brother, younger sister and nephew have also undergone repeated colonoscopic polypectomies at other clinics. His sister and nephew underwent genetic testing, and the same BMPR1A variant was identified.

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