Correction: Variant classification changes over time in BRCA1 and BRCA2

Mighton, Chloe; Charames, George S.; Wang, Marina; Zakoor, Kathleen-Rose; Wong, Andrew; Shickh, Salma; Watkins, Nicholas A.; Lebo, Matthew S.; Bombard, Yvonne; Lerner‐Ellis, Jordan

doi:10.1038/s41436-019-0526-x

Cited by 2 publications

(1 citation statement)

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“…One example of this is the reclassification for BRCA1 and BRCA2 variants over time, most often downgrading. 24,25 Traditionally the classification of (pathogenic) variants was based on the ascertainment from the more severe Mendelian disorders. Now, with more data available from population studies, reduced penetrance of variants is becoming clearer as is demonstrated by these kind of variants found in individuals without a Mendelian phenotype.…”

Section: Discussionmentioning

confidence: 99%

Reduced penetrance of pathogenic ACMG variants in a deeply phenotyped cohort study and evaluation of ClinVar classification over time

Rooij

Arp

Broer

et al. 2020

Genetics in Medicine

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Purpose: We studied the penetrance of pathogenically classified variants in an elderly Dutch population from the Rotterdam Study, for which deep phenotyping is available. We screened the 59 actionable genes for which reporting of known pathogenic variants was recommended by the American College of Medical Genetics and Genomics (ACMG), and demonstrate that determining what constitutes a known pathogenic variant can be quite challenging. Methods: We defined "known pathogenic" as classified pathogenic by both ClinVar and the Human Gene Mutation Database (HGMD). In 2628 individuals, we performed exome sequencing and identified known pathogenic variants. We investigated the clinical records of carriers and evaluated clinical events during 25 years of follow-up for evidence of variant pathogenicity. Results: Of 3815 variants detected in the 59 ACMG genes, 17 variants were considered known pathogenic. For 14/17 variants the ClinVar classification had changed over time. Of 24 confirmed carriers of these variants, we observed at least one clinical event possibly caused by the variant in only three participants (13%). Conclusion: We show that the definition of "known pathogenic" is often unclear and should be approached carefully. Additionally variants marked as known pathogenic do not always have clinical impact on their carriers. Definition and classification of true (individual) expected pathogenic impact should be defined carefully.

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Section: Discussionmentioning

confidence: 99%