The ClinGen Brain Malformation Variant Curation Expert Panel: Rules for somatic variants in AKT3, MTOR, PIK3CA, and PIK3R2

Published:August 22, 2022DOI:



      Postzygotic (somatic) variants in the mTOR pathway genes cause a spectrum of distinct developmental abnormalities. Accurate classification of somatic variants in this group of disorders is crucial for affected individuals and their families.


      The ClinGen Brain Malformation Variant Curation Expert Panel was formed to curate somatic variants associated with developmental brain malformations. We selected the genes AKT3, MTOR, PIK3CA, and PIK3R2 as the first set of genes to provide additional specifications to the 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) sequence variant interpretation guidelines, which currently focus solely on germline variants.


      A total of 24 of the original 28 ACMG/AMP criteria required modification. Several modifications used could be applied to other genes and disorders in which somatic variants play a role: 1) using variant allele fraction differences as evidence that somatic mutagenesis occurred as a proxy for de novo variation, 2) incorporating both somatic and germline evidence, and 3) delineating phenotype on the basis of variable tissue expression.


      We have established a framework for rigorous interpretation of somatic mosaic variants, addressing issues unique to somatic variants that will be applicable to many genes and conditions.


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