Publications by authors named "Megan Holdren"
Article Synopsis
- 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.
Article Synopsis
- PMS2 is a critical gene for DNA-mismatch repair linked to Lynch syndrome and certain cancers, making it a key target in genetic testing.
- The presence of the similar pseudogene PMS2CL complicates the sequencing process, often requiring costly long-read strategies instead of traditional methods.
- The article introduces a new bioinformatics workflow that can streamline PMS2 testing, eliminating the need for these more complex and expensive approaches for most patients.
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.
View Article and Find Full Text PDFVariants of uncertain significance (VUSs) in BRCA2 are a common result of hereditary cancer genetic testing. While more than 4,000 unique VUSs, comprised of missense or intronic variants, have been identified in BRCA2, the few missense variants now classified clinically as pathogenic or likely pathogenic are predominantly located in the region encoding the C-terminal DNA binding domain (DBD). We report on functional evaluation of the influence of 462 BRCA2 missense variants affecting the DBD on DNA repair activity of BRCA2 using a homology-directed DNA double-strand break repair assay.
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