Publications by authors named "Karl Krahn"
Background: Diffuse gastric and lobular breast cancer (LBC) syndrome is an autosomal-dominant syndrome characterised by early-onset diffuse gastric cancer and LBC most often caused by germline pathogenic variants (PVs) in . We previously showed the International Gastric Cancer Linkage Consortium (IGCLC) criteria for genetic testing to have poor sensitivity for PV and proposed our own simpler and more sensitive Yale criteria. The European Reference Network on Genetic Tumour Risk Syndromes subsequently proposed expanding the IGCLC criteria and showed its LBC-expanded criteria to be more sensitive than the IGCLC criteria in a European cohort of PV carriers.
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- - Pathogenic variants in the APC gene are responsible for familial adenomatous polyposis, the most common hereditary gastrointestinal polyposis syndrome, prompting the development of specific classification criteria to aid in variant interpretation.
- - The study involved applying these APC-specific criteria to assess over 10,000 unique APC variants from databases like ClinVar and LOVD, leading to a significant reclassification of variants of uncertain significance (VUSs), with many being reassessed as (likely) benign or (likely) pathogenic.
- - The results showed that using these tailored criteria effectively reduced VUSs by 37%, highlighted the potential for systematic variant classification in large datasets, and established a model that could benefit future genetic variant interpretation efforts in
Article Synopsis
- The study focused on improving the classification of genetic variants linked to familial adenomatous polyposis using APC-specific criteria developed by an expert panel.
- A total of 10,228 unique variants were analyzed, resulting in 41% of VUS from ClinVar and 61% from LOVD being reclassified, primarily as (Likely) Benign, which reduced the overall VUS by 37%.
- The research highlighted a systematic approach to variant classification in large datasets that could be applied to other gene/disease interpretations and allowed for prioritization of VUS requiring further evidence collection.