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.

PTEN Promoter Variants Are Not Associated With Common Cancers: Implications for Multigene Panel Testing

2017 ◽  
pp. 1-7 ◽  
Author(s):  
Mary Helen Black ◽  
Shuwei Li ◽  
Tina Pesaran ◽  
Holly LaDuca ◽  
Rachid Karam ◽  
...  
Keyword(s):  
Personal History ◽  
Variants Of Unknown Significance ◽  
Panel Testing ◽  
Multiple Primary ◽  
Unknown Significance ◽  
Uterine Endometrial Cancer ◽  
History Of ◽  
Race Ethnicity ◽  
Multigene Panel Testing ◽  
Multigene Panel

Purpose PTEN mutations are associated with breast, colon, endometrial, kidney, and thyroid cancers. Most PTEN promoter alterations, however, are characterized as variants of unknown significance, and their contribution to cancer risk is unclear. Materials and Methods Personal and family histories of 88,333 patients undergoing PTEN analysis as part of multigene panel testing (MGPT) were retrospectively reviewed. Cases (n = 59,784) were individuals with personal history of PTEN-related cancer. Controls (n = 28,549) had no personal history of cancer. Individuals were categorized as positive for one or more mutations (PATHO), without mutations but carrying one or more promoter variant (PROM), or negative for alterations (WT). Multivariable logistic regression was used to assess PTEN associations with phenotypes, adjusted for race/ethnicity, age, sex, and MGPT. Results Overall, 79 (0.09%) patients were PATHO and 791 (0.9%) were PROM carriers. Compared with WT, PATHOs were 2.30 (95% CI, 1.19 to 4.72) times as likely to have breast, 7.23 (95% CI, 2.74 to 19.14) times as likely to have bilateral/multiple primary breast, and 7.56 (95% CI, 1.97 to 23.98) times as likely to have uterine/endometrial cancer. PROMs were not significantly more likely than WT to have cancer (all 0.84 < odds ratio < 1.15; P > .05). Conclusion PTEN promoter variants were not associated with cancer. These results do not support the inclusion of PTEN promoter sequencing in MGPT.

scholarly journals Variants in HNRNPDL and SETX Not Necessarily Indicate Familial Amyotrophic Lateral Sclerosis or Limb Girdle Muscular Dystrophy 1G in Acute Muscular Respiratory Failure

2020 ◽  
Vol 11 (02) ◽  
pp. 353-354
Author(s):  
Josef Finsterer ◽  
Claudia Stöllberger ◽  
Hans Keller ◽  
Franco Laccone
Keyword(s):  
Respiratory Failure ◽  
Variants Of Unknown Significance ◽  
Non Invasive ◽  
Non Invasive Ventilation ◽  
Unknown Significance ◽  
History Of ◽  
History Of Epilepsy ◽  
Diagnostic Work ◽  
Conclusive Diagnosis ◽  
Work Up

AbstractGenetic work-up is useful for the identification of a primary myopathy. However, even sophisticated genetic methods may fail to detect the underlying cause of myopathy as in the following case. The patient is a 52-year-old female with a history of epilepsy, arterial hypertension, atrial flutter requiring cardioversion, ablation, and anticoagulation, coronary heart disease, hyperlipidemia, and hyper-CKemia. At age 52 years, she was referred for heart failure due to ischemic cardiomyopathy requiring appropriate medication and implantation of an ICD. During hospitalization she developed acute muscular respiratory failure requiring mechanical ventilation. Genetic panels for myopathy, neuropathy, and cardiomyopathy revealed variants of unknown significance in the HNRNPDL and SETX genes respectively. Clinical presentation and muscle biopsy, however, suggested metabolic myopathy. Acute muscular respiratory failure may require traditional diagnostic work-up for primary myopathy and long-term invasive and non-invasive ventilation. Panel investigations not necessarily lead to a conclusive diagnosis. The multisystem nature of the condition rather suggests a metabolic defect than LGMD-1G or fALS as genetic findings suggested.

The incidence of BRCA1 and BRCA2 variants of unknown significance varies in different ethnic populations

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10002-10002 ◽  
Author(s):  
D. M. Opatt ◽  
M. Morrow ◽  
M. Daly
Keyword(s):  
Breast Cancer ◽  
African American ◽  
Genetic Testing ◽  
African American Women ◽  
White Women ◽  
Personal History ◽  
Brca1 And Brca2 ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
History Of

10002 Background: BRCA1 and BRCA2 mutations in the general population are rare. Women with these mutations have a significantly increased risk of invasive breast and ovarian cancer (65–85% and 15–65% cumulative lifetime risk, respectively). Variants of unknown significance (VUS), which are of uncertain clinical importance, account for up to 50% of all identified BRCA1 and BRCA2 sequence alterations1. Methods: Pooled data from all patients presenting to Fox Chase Cancer Center for genetic counseling was examined. Patients underwent genetic testing after detailed genetic counseling. Clinical data, including gender, ethnic background, and personal history of cancer, and total number of patients tested were collected. Results: A total of 1,765 women and 236 men underwent genetic testing. The distribution of ethnicity was: <1% Asian, 2.7% African American, <1% Hispanic, 2.4% other or of more than one ethnicity, 83% White, and 11% unknown. Mutations of BRCA1 and BRCA2 were seen in 13% of the women and 2.7% of the men. VUS were seen in 6.2% of the women and .15% of the men. Of the women positive for a VUS, 2.4% were Asian, 18.1% were African American, 5.5% were Hispanic, 4.7% were more than one ethnicity, 66.9% were White, and 2.4% were Unknown ethnicity. Only .15% of the men tested were positive for a VUS, all of whom were White. Of the 51 African American women tested, 45.1% were positive for a VUS while only 5.5% of the 1,503 White women tested were positive (p<0.0001). Of the females testing positive for a VUS, a personal history of breast cancer was seen in 66.7% of Asians, 78.3% of African Americans, 100% of Hispanics, 83.3% of those more than one race, 61% of Whites, and none of the people of unknown ethnic origin. One of three men testing positive for a VUS reported a history of breast cancer. Conclusions: Identification of VUS occurred disproportionately in African Americans, occurring ten times more often in African American women than White women in our study. Studies to improve classification of VUS as deleterious or neutral are needed to enhance the utility of genetic testing for women at risk, particularly those of African American ethnicity. 1Goldman, DE et al. Am. J. Hum. Genet., 2004. No significant financial relationships to disclose.

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 a heterozygous p.Gly568Val missense mutation in the TRPV3 gene in a Japanese patient with Olmsted syndrome: In silico analysis of TRPV3

2017 ◽  
Vol 44 (9) ◽  
pp. 1059-1062 ◽  
Author(s):  
Hiroshi Nagai ◽  
Yutaka Takaoka ◽  
Aki Sugano ◽  
Yuji Nakamachi ◽  
Seiji Kawano ◽  
...  
Keyword(s):  
Missense Mutation ◽  
In Silico ◽  
Japanese Patient ◽  
In Silico Analysis ◽  
Silico Analysis

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.

scholarly journals Variations in AXIN2 predict risk and prognosis of colorectal cancer

BDJ Open ◽  
2019 ◽  
Vol 5 (1) ◽  
Author(s):  
L. Otero ◽  
E. Lacunza ◽  
V. Vasquez ◽  
V. Arbelaez ◽  
F. Cardier ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
In Silico ◽  
Familial Cancer ◽  
In Silico Analysis ◽  
Healthy Individuals ◽  
R Software ◽  
Chi Square ◽  
History Of ◽  
Silico Analysis ◽  
Worse Prognosis

Abstract Objective Colorectal cancer (CRC) and hypodontia are frequent and different diseases with common genes are involved in their etiology. The objective of this study was to identify the association between AXIN2 rs2240308 with hypodontia and CRC. Patients and methods This study consisted of 50 individuals with hypodontia, 50 individuals with CRC, and 155 healthy individuals from Colombia. SNP genotyping assays of rs2240308 were performed and family history of cancer in individuals with hypodontia was documented. In silico analysis was implemented to define the genomic profile of the AXIN2 gene associated with CRC. Multivariate analysis, chi square, odd ratio tests, and R software were used for statistical analysis. Results AXIN2 rs2240308 showed association with CRC (OR = 5.4 CI: 2.7–10.4; p < 0.001) and with other familial cancer in individuals with hypodontia (p < 0.005 OR = 1.75, 95% CI: 1.22–6.91). In silico analysis showed that variations in AXIN2 found in CRC patients, were more frequently in earlier stages of tumor and patients who carry variations in the AXIN2 gene have a worse prognosis (p < 0.05). The association between AXIN2 rs2240308 with hypodontia was not significant. Conclusions These results suggest that AXIN2 rs2240308 polymorphism is associated with CRC and AXIN2 could be a risk marker for predisposition and prognosis of CRC.

scholarly journals Two Rare Variants in PLAU and BACE1 Genes—Do They Contribute to Semantic Dementia Clinical Phenotype?

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1806
Author(s):  
Katarzyna Gaweda-Walerych ◽  
Emilia J. Sitek ◽  
Małgorzata Borczyk ◽  
Mariusz Berdyński ◽  
Ewa Narożańska ◽  
...  
Keyword(s):  
Early Onset ◽  
Rare Variants ◽  
Missense Variant ◽  
Underlying Mechanism ◽  
Semantic Dementia ◽  
Mrna Levels ◽  
Protein Levels ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
History Of

We have performed whole-genome sequencing to identify the genetic variants potentially contributing to the early-onset semantic dementia phenotype in a patient with family history of dementia and episodic memory deficit accompanied with profound semantic loss. Only very rare variants of unknown significance (VUS) have been identified: a nonsense variant c.366C>A/p.Cys122* in plasminogen activator, urokinase (PLAU) and a missense variant c.944C>T/p.Thr315Met in β-site APP-cleaving enzyme 1 (BACE1)—along with known disease-modifying variants of moderate penetrance. Patient-derived fibroblasts showed reduced PLAU and elevated BACE1 mRNA and protein levels compared to control fibroblasts. Successful rescue of PLAU mRNA levels by nonsense-mediated mRNA decay (NMD) inhibitor (puromycin) confirmed NMD as the underlying mechanism. This is the first report of the PLAU variant with the confirmed haploinsufficiency, associated with semantic dementia phenotype. Our results suggest that rare variants in the PLAU and BACE1 genes should be considered in future studies on early-onset dementias.

scholarly journals Novel homozygous HEXB mutation identified in a consanguineous Iranian pedigree with Sandhoff disease

2020 ◽  
Author(s):  
Zahra Rahmani ◽  
Arsham Banisadr ◽  
Vadieh Ghodsinezhad ◽  
Mohsen Dibaj ◽  
Omid Aryani
Keyword(s):  
Autosomal Recessive ◽  
In Silico Analysis ◽  
Autosomal Recessive Disorder ◽  
Sandhoff Disease ◽  
Normal Activity ◽  
Ganglioside Metabolism ◽  
History Of ◽  
Biochemical Testing ◽  
Hexb Gene ◽  
Silico Analysis

Abstract Background Sandhoff disease is a rare neurodegenerative and autosomal recessive disorder, characterized by a defect in ganglioside metabolism. It is caused by mutations in the HEXB gene for the β-subunit of β-N-acetyl hexosaminidase. Results In the present study, an Iranian 14- month -old girl with an 8- month history of unsteady walking and involuntary movements is described. Biochemical testing showed defects in the normal activity of beta-hexosaminidase protein. Following sequencing of HEXB gene, a novel homozygous p.A278V mutation was identified in the patient’s DNA. Conclusions The p.A278V mutation is pathogenic because of amino acid change and changing in biochemical activity. this mutation has not been reported previously, but based on In silico analysis and structural analysis, was predicted to be disease causing.

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