Publications by authors named "M de la Hoya"
Background: TP53 variant classification benefits from the availability of large-scale functional data for missense variants generated using cDNA-based assays. However, absence of comprehensive splicing assay data for TP53 confounds the classification of the subset of predicted missense and synonymous variants that are also predicted to alter splicing. Our study aimed to generate and apply splicing assay data for a prioritised group of 59 TP53 predicted missense or synonymous variants that are also predicted to affect splicing by either SpliceAI or MaxEntScan.
View Article and Find Full Text PDFGermline BRCA2 loss-of function variants, which can be identified through clinical genetic testing, predispose to several cancers. However, variants of uncertain significance limit the clinical utility of test results. Thus, there is a need for functional characterization and clinical classification of all BRCA2 variants to facilitate the clinical management of individuals with these variants.
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- The ClinGen Hereditary Breast, Ovarian, and Pancreatic Cancer Variant Curation Expert Panel (HBOP VCEP) created specific guidelines for interpreting variants in the ATM gene, modifying the American College of Medical Genetics and Association for Molecular Pathology (ACMG/AMP) guidelines.
- A pilot study testing 33 variants showed strong agreement between the VCEP classifications and existing ClinVar data, though some conflicting interpretations were clarified.
- Overall, the modified rules led to 85% of the variants being classified more definitively, significantly enhancing the reliability of genetic interpretations related to the ATM gene.
Article Synopsis
- The ENIGMA research consortium focuses on determining the clinical significance of variants in hereditary breast and ovarian cancer genes, specifically BRCA1 and BRCA2, and evolved from an external expert panel to an internal Variant Curation Expert Panel (VCEP) to enhance alignment with FDA recognized classification processes.
- The VCEP reviewed existing classification criteria and utilized statistical methods to assess evidence strength, testing new specifications on variants and updating documentation for better user clarity.
- Analysis led to refined classifications for variants—resolving uncertainties and maintaining confidence in others—while revealing gaps in both ENIGMA's research and ACMG/AMP criteria, ultimately improving the classification process for BRCA1 and BRCA2 variants.
The ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer (HBOP) Variant Curation Expert Panel (VCEP) is composed of internationally recognized experts in clinical genetics, molecular biology and variant interpretation. This VCEP made specifications for ACMG/AMP guidelines for the ataxia telangiectasia mutated () gene according to the Food and Drug Administration (FDA)-approved ClinGen protocol. These gene-specific rules for were modified from the American College of Medical Genetics and Association for Molecular Pathology (ACMG/AMP) guidelines and were tested against 33 variants of various types and classifications in a pilot curation phase.
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