scholarly journals Genetic Variants and Somatic Alterations Associated with MITF-E318K Germline Mutation in Melanoma Patients

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1440
Author(s):  
Elisabetta Vergani ◽  
Simona Frigerio ◽  
Matteo Dugo ◽  
Andrea Devecchi ◽  
Erika Feltrin ◽  
...  
Keyword(s):  
In Silico Analysis ◽  
Braf V600e ◽  
Variants Of Unknown Significance ◽  
Whole Exome ◽  
Number Of Patients ◽  
Clinical Strategies ◽  
Unknown Significance ◽  
Somatic Alterations ◽  
Melanoma Patients ◽  
Tumor Genome

The MITF-E318K variant has been implicated in genetic predisposition to cutaneous melanoma. We addressed the occurrence of MITF-E318K and its association with germline status of CDKN2A and MC1R genes in a hospital-based series of 248 melanoma patients including cohorts of multiple, familial, pediatric, sporadic and melanoma associated with other tumors. Seven MITF-E318K carriers were identified, spanning every group except the pediatric patients. Three carriers showed mutated CDKN2A, five displayed MC1R variants, while the sporadic carrier revealed no variants. Germline/tumor whole exome sequencing for this carrier revealed germline variants of unknown significance in ATM and FANCI genes and, in four BRAF-V600E metastases, somatic loss of the MITF wild-type allele, amplification of MITF-E318K and deletion of a 9p21.3 chromosomal region including CDKN2A and MTAP. In silico analysis of tumors from MITF-E318K melanoma carriers in the TCGA Pan-Cancer-Atlas dataset confirmed the association with BRAF mutation and 9p21.3 deletion revealing a common genetic pattern. MTAP was the gene deleted at homozygous level in the highest number of patients. These results support the utility of both germline and tumor genome analysis to define tumor groups providing enhanced information for clinical strategies and highlight the importance of melanoma prevention programs for MITF-E318K patients.

Whole‐Exome Sequencing of a Saudi Epilepsy Cohort Reveals Association Signals in Known and Potentially Novel Loci

2021 ◽  
Author(s):  
Amein Kadhem AlAli ◽  
Abdulrahman Al-Enazi ◽  
Ahmed Ammar ◽  
Mahmoud Hajj ◽  
Cyril Cyrus ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Variants ◽  
High Rate ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Novel Variants ◽  
Unknown Significance ◽  
Rare Genetic Variants

Abstract Background Epilepsy, a serious chronic neurological condition effecting up to 100 million people globally, has clear genetic underpinnings including common and rare variants. In Saudi Arabia the prevalence of epilepsy is high and caused mainly by perinatal and genetic factors. No whole-exome sequencing (WES) studies have been performed to date in Saudi Arabian Epilepsy cohorts. This offers a unique opportunity for the discovery of rare genetic variants impacting this disease as there is a high rate of consanguinity amongst large tribal pedigrees. Results We performed WES on 144 individuals diagnosed with epilepsy, to interrogate known Epilepsy related genes for known and functional novel variants. We also used an American College of Medical Genetics (ACMG) guideline based variant prioritization approach in an attempt to discover putative causative variants. We identified a 32 potentially causative pathogenic variants across 30 different genes in 44/144 (30%) of these Saudi Epilepsy individuals. We also identified 232 variants of unknown significance (VUS) across 101 different genes in 133/144 (92%) subjects. Strong enrichment of variants of likely pathogenicity were observed in previously described epilepsy-associated loci, and a number of putative pathogenic variants in novel loci are also observed. Conclusion Several putative pathogenic variants known to be epilepsy-related loci were identified for the first time in our population, in addition to several potential new loci have been identified which may be prioritized for further investigation.

Prediction of olaparib sensitivity for variants of unknown significance in homologous repair genes.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3108-3108
Author(s):  
Sandy Chevrier ◽  
Isabelle Desmoulins ◽  
Laure Favier ◽  
François Ghiringhelli ◽  
Leila Bengrine ◽  
...  
Keyword(s):  
Parp Inhibitor ◽  
Brca2 Mutation ◽  
Parp Inhibitors ◽  
Allelic Frequency ◽  
Prediction Algorithm ◽  
Bioinformatics Analyses ◽  
Variants Of Unknown Significance ◽  
Number Of Patients ◽  
Unknown Significance ◽  
Repair Genes

3108 Background: the recent use of PARP inhibitors in clinical practice gives very interesting outcome for ovary tumors with BRCA1 or BRCA2 mutation but also in other tumors with homologous repair deficiency. Nevertheless, no hotspot mutations are present, consequently, more than 85% of observed variants have unknown significance, blocking the use of PARP inhibitor. Methods: Exome analysis was performed on a cohort of 27 patients treated with olaparib. After bioinformatics analyses, variant interpretation was performed by interrogating different databases. For variants of unknown significance (VUS), PROVEAN software and allelic frequency normalized with tumor cellular content were used to classify VUS as potentially benign or potentially deleterious. Results: Among the 27 patients analyzed, 16 harbored already classified variants (3 benign and 13 pathogen variants) and 11 had VUS. The first Progression Free Survival (PFS) analysis showed that benign variants did not respond to olaparib with a median survival of 62 days, whereas pathogenic variants had a median of 109 days. Surprisingly, VUS had a median of 136 days, suggesting that some of them could be classified as potentially deleterious. On the subset of 11 patients with VUS, we applied PROVEAN prediction classifying 5 variants as benign and 6 variants as deleterious, with a median PFS of 54 days and 140 days ( p=0.3235), respectively. With the second prediction, based on variant allelic frequency, we obtained PFS of 73.5 months for benign variants and 210 days for deleterious ones ( p=0.29). By combining both predictions, we classified as benign, VUS predicted benign with both predictions, and as deleterious, VUS predicted as deleterious with at least one prediction. Consequently, we perfectly discriminated benign from deleterious variants with a median PFS of 36 days for predicted benign and 177 days for predicted deleterious ( p=0.0084). From all patients, PFS were significantly different ( p=0.0003) between benign (n=6, 56 days) and deleterious variants (n=21, 140 months). Conclusions: Our work tends to show that VUS of homologous repair genes could be predicted as benign or deleterious, and could increase the number of patients eligible for a treatment by PARP inhibitors. The number of patients needs to be increased in order to validate our prediction algorithm.

scholarly journals In silico analysis of BRCA1 and BRCA2 missense variants and the relevance in molecular genetic testing

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kok-Siong Poon
Keyword(s):  
Genetic Testing ◽  
Molecular Genetic ◽  
In Silico Analysis ◽  
Molecular Testing ◽  
Brca1 And Brca2 ◽  
Missense Variants ◽  
Variants Of Unknown Significance ◽  
Sorting Intolerant From Tolerant ◽  
Unknown Significance ◽  
High Concordance

AbstractOver the years since the genetic testing of BRCA1 and BRCA2 has been conducted for research and later introduced into clinical practice, a high number of missense variants have been reported in the literature and deposited in public databases. Polymorphism Phenotyping v2 (PolyPhen-2) and Sorting Intolerant from Tolerant (SIFT) are two widely applied bioinformatics tools used to assess the functional impacts of missense variants. A total of 2605 BRCA1 and 4763 BRCA2 variants from the ClinVar database were analysed with PolyPhen2 and SIFT. When SIFT was evaluated alongside PolyPhen-2 HumDiv and HumVar, it had shown top performance in terms of negative predictive value (NPV) (100%) and sensitivity (100%) for ClinVar classified benign and pathogenic BRCA1 variants. Both SIFT and PolyPhen-2 HumDiv achieved 100% NPV and 100% sensitivity in prediction of pathogenicity of the BRCA2 variants. Agreement was achieved in prediction outcomes from the three tested approaches in 55.04% and 68.97% of the variants of unknown significance (VUS) for BRCA1 and BRCA2, respectively. The performances of PolyPhen-2 and SIFT in predicting functional impacts varied across the two genes. Due to lack of high concordance in prediction outcomes among the two tested algorithms, their usefulness in classifying the pathogenicity of VUS identified through molecular testing of BRCA1 and BRCA2 is hence limited in the clinical setting.

Identification of novel missense mutation in a patient with an asymptomatic para-aortic paraganglioma

2021 ◽  
Vol 14 (10) ◽  
pp. e245427
Author(s):  
Salah Daghlas ◽  
Rajani Gundluru ◽  
Ayman Nada ◽  
Uzma Khan
Keyword(s):  
Missense Mutation ◽  
In Silico Analysis ◽  
Caucasian Woman ◽  
Donor Kidney ◽  
Urinary Catecholamines ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
History Of ◽  
Silico Analysis ◽  
Kidney Transplant Donor

A 31-year-old Caucasian woman underwent a standard workup as a potential kidney transplant donor. Kidney donor protocol CT showed a left para-aortic hypervascular mass suspicious for a paraganglioma. Biochemical workup revealed elevated urinary catecholamines, supporting this suspicion. The patient underwent surgical resection with histopathological evaluation that confirmed the diagnosis. Endocrine evaluation 2 years later revealed a family history of a cousin with a history of pheochromocytoma as a teenager. A genetic panel identified a missense mutation in succinate dehydrogenase C (c.202T>C; p.Ser68Pro), which was described as a variant of unknown significance. In silico analysis suggested that it may be a deleterious mutation. We concluded that this mutation may be pathogenic, considering these supporting pieces of evidence and her early-onset paraganglioma. This report highlights the importance of genetic screening in patients with paragangliomas/pheochromocytomas, since many cases are familial. Additionally, it underscores the importance of evaluating and documenting cases of variants of unknown significance.

Abstract 12059: Incidental Findings in Cardiomyopathy and Channelopathy Genes Among 5891 Individuals Undergoing Whole-exome Sequencing. What Should be Reported?

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Elisa Mastantuono ◽  
Thomas Wieland ◽  
Riccardo Berutti ◽  
Peter Lichtner ◽  
Tim Strom ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Incidental Findings ◽  
Genetic Disorders ◽  
Molecular Diagnostic ◽  
Minor Genes ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Unknown Significance

Background: Whole-exome-sequencing (WES) is becoming a common molecular diagnostic test for patients with genetic disorders. However, this technique allows the identification not only of mutations responsible for the disease under investigation, but also of variants potentially causing other diseases, the so called “incidental findings” (IFs). The American College of Medical Genetics and Genomics (ACMG) stated that IFs should be reported based on clinical validity and utility and indicated a list of 56 actionable genes. Among these, nearly half (20/56) are major genes associated with channelopathies and cardiomyopathies. Despite these recommendations, most of the studies so far published, reported also mutations in minor genes among the actionable findings. Methods: WES was performed in 5891 individuals without known channelopathies or cardiomyopathies. Exome data were first filtered based on genotype quality. Subsequently, a frequency filter was applied, considering 1000 Genomes, ExAC and our internal exome database. Variants reported as pathogenic in ClinVar or novel but expected to be pathogenic (nonsense, frameshift and splice) were further investigated, following the ACMG guidelines. Major (20) and minor (73) genes associated with channelopathies and cardiomyopathies were evaluated. Results: We identified 3514 variants in the 93 genes under investigation, after applying the quality and frequency filters. Eight variants were classified as pathogenic and 52 as likely pathogenic and they were detected in around 1% of the individuals. The vast majority (85%) of pathogenic or likely pathogenic variants were located in the 20 actionable genes indicated by ACMG. The inclusion of minor genes increased the number of variants of unknown significance (VUS), from 865 to 3454. Conclusion: Our data support the ACMG recommendations in reporting only IFs identified in the 20 major cardiac actionable genes. Indeed, the inclusion of minor genes is mainly increasing the number of VUS, without significantly impacting the number of pathogenic and likely pathogenic variants. The percentage of individuals with potentially clinical relevant variants in these genes is too high in relation to the disease-prevalence: a cardiologic evaluation is warranted.

scholarly journals The challenge of consent in clinical genome-wide testing

2016 ◽  
Vol 101 (11) ◽  
pp. 1048-1052 ◽  
Author(s):  
Katherine Burke ◽  
Angus Clarke
Keyword(s):  
Comparative Genomic Hybridisation ◽  
Comparative Genomic ◽  
Testing Methods ◽  
Multiple Gene ◽  
Variants Of Unknown Significance ◽  
Genome Wide ◽  
Whole Exome ◽  
Unknown Significance ◽  
Gene Panels ◽  
Wide Testing

Genome-wide testing methods include array comparative genomic hybridisation (aCGH), multiple gene panels, whole exome sequencing (WE) and whole genome sequencing (WGS). Here we introduce some of the key ethical and social considerations relating to informed consent for the testing of children, particularly the management of incidental findings and variants of unknown significance.

QOLP-16. PATIENT-REPORTED SELECTION FOR INCIDENTAL FINDINGS IN A COMPREHENSIVE GENOMIC TRIAL: A DANISH SINGLE INSTITUTION EXPERIENCE FROM THE COPENHAGEN GLIOBLASTOMA COHORT

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi186-vi186
Author(s):  
Dorte Schou Nørøxe ◽  
Hans Poulsen ◽  
Ulrik Lassen
Keyword(s):  
Clinical Trials ◽  
Incidental Findings ◽  
Trial Participation ◽  
Full Information ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Complex Information ◽  
Whole Exome ◽  
Patient Reported ◽  
Unknown Significance

Abstract INTRODUCTION Participation in clinical trials is a high priority in the neuro oncology community and requires an informed, signed consent. However, patient information is increasingly complex as many trials include comprehensive molecular analyses and, according to Danish legislation, must include a statement about incidental findings. Incidental findings can range from variants of unknown significance to pathogenic variants in the mismatch repair-genes (MMR) and BRCA1-2. Pathogenic variants have been reported in 1-18% of cancers and can have significant influence for the patient and family. Patients with glioblastoma (GBM) can have impaired cognitive function, both due to GBM and due to morbidity after surgery. This can limit access to clinical trials as some patients might not understand the study information. We investigated whether patients were interested in participating in a comprehensive genomic trial and where they marked their preference of information for incidental findings. PATIENTS AND METHODS 108 consents from a published study from the Copenhagen Glioblastoma Cohort were examined. The study period was 2016-2019 and included whole exome- and RNA sequencing. The consent included three alternatives to receive information about incidental findings; 1) none, 2) if incidental findings could be treated or future disease be prevented or 3) full information even though no treatment or prevention existed. RESULTS A total of 108/111 (97.3%) patients consented to participate. Each category was marked as follows: 33 (30.6%) marked 1), 24 (22.2%) marked 2) and 45 patients (41.7%) marked 3), respectively. Six consents were N/A as either two or no boxes were marked. No pathogenic incidental findings were identified. CONCLUSION We found a high interest in trial participation despite of complex study information. Information about incidental findings was spread between groups with majority of patients interested in receiving full information, suggesting that complex information does not hinder participation in molecular-based trials for GBM patients.

scholarly journals Sorting Variants of Unknown Significance Identified by Whole Exome Sequencing: Genetic and Laboratory Investigations of Two Novel MCT8 Variants

Thyroid ◽  
2020 ◽  
Vol 30 (3) ◽  
pp. 463-465 ◽  
Author(s):  
Jiao Fu ◽  
Manassawee Korwutthikulrangsri ◽  
Leigh Ramos-Platt ◽  
Tyler M. Pierson ◽  
Xiao Hui Liao ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Variants Of Unknown Significance ◽  
Whole Exome ◽  
Unknown Significance ◽  
Laboratory Investigations

scholarly journals Child Neurology: Siblings with infantile epilepsy and developmental delay

Neurology ◽  
2018 ◽  
Vol 91 (3) ◽  
pp. 143-147
Author(s):  
Yin Liu ◽  
David Michelson ◽  
Robin Clark ◽  
June-Anne Gold
Keyword(s):  
Developmental Delay ◽  
Intractable Epilepsy ◽  
Deletion Syndrome ◽  
Genomic Disorder ◽  
Germline Mosaicism ◽  
Variants Of Unknown Significance ◽  
Whole Exome ◽  
Unknown Significance ◽  
Infantile Epilepsy

ObjectiveChromosome 14q11-q22 deletion syndrome (OMIM 613457) is a rare genomic disorder with a variable phenotype.MethodsWe report 2 full siblings, a brother and sister, with a unique familial 2.4 Mb microdeletion at 14q13.1–14q13.3 by microarray (first identified in the brother, Mayo Clinical Laboratories, 2010).ResultsBoth children presented with infantile spasms that evolved to intractable epilepsy and profound developmental delay. They share distinctive dysmorphic features: long expressionless facies, full cheeks, flattened midface, full lips, and generalized hypotonia. Only the sister has hemophagocytic lymphohistiocytosis (HLH). Testing in the brother revealed 3 variants of unknown significance (VUS) (Greenwood Genetics, epilepsy/seizure panel, 145 genes, 2015). The sister had normal results with a different gene panel (GeneDx, infantile epilepsy panel, 75 genes, 2016) but it did not include the 3 genes in which VUS were identified in her brother. Whole exome sequencing in the mother, father, and both siblings was negative without VUS (GeneDx, XomeDx, 2016). There were no variants within the deleted interval in the intact allele for both children. Parental fluorescent in situ hybridization studies for 14q13.1–14q13.3, done in 2017, were normal. Haplotype analysis of the intact chromosome 14 in the sister supported paternal origin for the deletion and likely germline mosaicism in the father. Haploinsufficiency of genes in the deleted region has not been associated with an abnormal phenotype.ConclusionsThese children have a specific, recognizable neurodevelopmental phenotype and 14q13 microdeletion. This report highlights the challenges of coordinating and interpreting genetic testing in syndromic epilepsy.

Sign in / Sign up

Export Citation Format

Share Document