scholarly journals Determination of Pathogenicity of Breast Cancer 1 Gene Variants using the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Guidelines

2019 ◽  
Vol 19 (4) ◽  
pp. 324
Author(s):  
Angela Brown ◽  
Mansour Zamanpoor ◽  
Donald R. Love ◽  
Debra O. Prosser
Keyword(s):  
Breast Cancer ◽  
New Zealand ◽  
Molecular Pathology ◽  
Brca1 Gene ◽  
Medical Genetics ◽  
Splice Donor Site ◽  
Molecular Diagnostic ◽  
Gene Variants ◽  
Genetics And Genomics

Objectives: Molecular diagnostic laboratories screen for mutations in disease-causing genes in order to confirm a clinical diagnosis. The classification of DNA variants as ‘pathogenic’ or ‘likely pathogenic’ mutations creates a workflow bottleneck, which becomes increasingly challenging as greater number of genes are screened. The classification challenge is also acute if there are conflicting reports regarding pathogenicity and differing classification criteria between laboratories. This study aimed to compare two procedures for the classification of variants in the breast cancer (BRCA)1 gene. Methods: This bioinformatic study was conducted at LabPLUS, Auckland, New Zealand, from February to June 2017. DNA was extracted from peripheral blood samples of 30 patients and gene library construction was carried out using a commercially available targeted panel for the BRCA1 and BRCA2 genes. The genes were subsequently sequenced and the sequence data analysed. The guidelines published by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/ AMP) provides a comprehensive framework for the interpretation of variants in genes that are associated with Mendelian disorders. The use of these guidelines were compared to the variant classifications that were achieved by reference to those reported in the BRCA Exchange database. Results: The results showed concordance between the two classification protocols for a panel of 30 BRCA1 gene variants, although the transparency in following the ACMG/AMP guidelines provides a diagnostic laboratory with a generalisable approach that allows laboratorydirected revisions to be undertaken in light of new information. Conclusion: The ACMG/AMP-based guidelines were applied to a cohort of patients with BRCA1 gene variants. The use of these guidelines provides a system which creates consistency in variant interpretation and supports subsequent clinical management.Keywords: BRCA1 Gene; Bioinformatics; DNA Sequencing; Nonsense Codon; Splice Donor Site; New Zealand.

scholarly journals Rare Variants Associated with Arrhythmogenic Cardiomyopathy: Reclassification Five Years Later

2021 ◽  
Vol 11 (3) ◽  
pp. 162 ◽  
Author(s):  
Marta Vallverdú-Prats ◽  
Mireia Alcalde ◽  
Georgia Sarquella-Brugada ◽  
Sergi Cesar ◽  
Elena Arbelo ◽  
...  
Keyword(s):  
Rare Variant ◽  
Rare Variants ◽  
Medical Genetics ◽  
Definite Diagnosis ◽  
Arrhythmogenic Cardiomyopathy ◽  
Genetic Interpretation ◽  
Genetics And Genomics

Genetic interpretation of rare variants associated with arrhythmogenic cardiomyopathy (ACM) is essential due to their diagnostic implications. New data may relabel previous variant classifications, but how often reanalysis is necessary remains undefined. Five years ago, 39 rare ACM-related variants were identified in patients with features of cardiomyopathy. These variants were classified following the American College of Medical Genetics and Genomics’ guidelines. In the present study, we reevaluated these rare variants including novel available data. All cases carried one rare variant classified as being of ambiguous significance (82.05%) or likely pathogenic (17.95%) in 2016. In our comprehensive reanalysis, the classification of 30.77% of these variants changed, mainly due to updated global frequencies. As in 2016, nowadays most variants were classified as having an uncertain role (64.1%), but the proportion of variants with an uncertain role was significantly decreased (17.95%). The percentage of rare variants classified as potentially deleterious increased from 17.95% to 23.07%. Moreover, 83.33% of reclassified variants gained certainty. We propose that periodic genetic reanalysis of all rare variants associated with arrhythmogenic cardiomyopathy should be undertaken at least once every five years. Defining the roles of rare variants may help clinicians obtain a definite diagnosis.

scholarly journals Understanding the Genome: Professional Guidelines in Clinical Genomic Testing and Interpretation

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. SCI-5-SCI-5
Author(s):  
Elaine Lyon
Keyword(s):  
Molecular Pathology ◽  
Rapid Evolution ◽  
Medical Genetics ◽  
Quality Data ◽  
Genomic Testing ◽  
Advisory Committees ◽  
Korean Society ◽  
Complete Genomics ◽  
Genetics And Genomics ◽  
Professional Guidelines

Abstract The rapid evolution of genomic testing gives new meaning to the term "high-complexity testing." Variant classification is clearly challenging, but with the aid of American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) professional guidelines for combining evidence used in conjunction with national efforts, laboratories may be better able to standardize and establish quality metrics. Additionally, guidelines for evaluating types of evidence and interpreting sequence variations have been developed. This session will review these guidelines to address expectations of data quality, as well as elements of reporting identified variants and their interpretations. Efforts by the molecular community to address consistency in using these guidelines will also be shown. The objectives of this presentation are to list technical guidelines for genomic sequencing to ensure quality data, to describe evidence used to classify variants, and to identify variability in how evidences are used. Disclosures Lyon: Complete Genomics: Consultancy; Korean Society for Medical and Molecular Genetics: Honoraria; Association for Molecular Pathology: Honoraria; American College of Medical Genetics and Genomics: Membership on an entity's Board of Directors or advisory committees.

scholarly journals APP, PSEN1, and PSEN2 Variants in Alzheimer’s Disease: Systematic Re-evaluation According to ACMG Guidelines

2021 ◽  
Vol 13 ◽  
Author(s):  
Xuewen Xiao ◽  
Hui Liu ◽  
Xixi Liu ◽  
Weiwei Zhang ◽  
Sizhe Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Pathology ◽  
Medical Genetics ◽  
Variants Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Pubmed Database ◽  
Uncertain Significance ◽  
Genetics And Genomics

The strategies of classifying APP, PSEN1, and PSEN2 variants varied substantially in the previous studies. We aimed to re-evaluate these variants systematically according to the American college of medical genetics and genomics and the association for molecular pathology (ACMG-AMP) guidelines. In our study, APP, PSEN1, and PSEN2 variants were collected by searching Alzforum and PubMed database with keywords “PSEN1,” “PSEN2,” and “APP.” These variants were re-evaluated based on the ACMG-AMP guidelines. We compared the number of pathogenic/likely pathogenic variants of APP, PSEN1, and PSEN2. In total, 66 APP variants, 323 PSEN1 variants, and 63 PSEN2 variants were re-evaluated in our study. 94.91% of previously reported pathogenic variants were re-classified as pathogenic/likely pathogenic variants, while 5.09% of them were variants of uncertain significance (VUS). PSEN1 carried the most prevalent pathogenic/likely pathogenic variants, followed by APP and PSEN2. Significant statistically difference was identified among these three genes when comparing the number of pathogenic/likely pathogenic variants (P < 2.2 × 10–16). Most of the previously reported pathogenic variants were re-classified as pathogenic/likely pathogenic variants while the others were re-evaluated as VUS, highlighting the importance of interpreting APP, PSEN1, and PSEN2 variants with caution according to ACMG-AMP guidelines.

Model for Classification of ChEMBL Dataset of Anti-breast cancer Compounds According to Multiple Pharmacological Parameters, Biological Assays, and Receptors

2015 ◽  
Vol 13 (999) ◽  
pp. 1-1
Author(s):  
Francisco J. Prado-Prado ◽  
Angel G. Arguello-Chan ◽  
Coraima I. Estrada-Domínguez ◽  
Alejandra Aguirre-Crespo ◽  
Francisco J. Aguirre-Crespo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Biological Assays
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