TY - JOUR
T1 - The ClinGen Brain Malformation Variant Curation Expert Panel
T2 - Rules for somatic variants in AKT3, MTOR, PIK3CA, and PIK3R2
AU - ClinGen Brain Malformation Variant Curation Expert Panel
AU - Lai, Abbe
AU - Soucy, Aubrie
AU - El Achkar, Christelle Moufawad
AU - Barkovich, Anthony J.
AU - Cao, Yang
AU - DiStefano, Marina
AU - Evenson, Michael
AU - Guerrini, Renzo
AU - Knight, Devon
AU - Lee, Yi Shan
AU - Mefford, Heather C.
AU - Miller, David T.
AU - Mirzaa, Ghayda
AU - Mochida, Ganesh
AU - Rodan, Lance H.
AU - Patel, Mayher
AU - Smith, Lacey
AU - Spencer, Sara
AU - Walsh, Christopher A.
AU - Yang, Edward
AU - Yuskaitis, Christopher J.
AU - Yu, Timothy
AU - Poduri, Annapurna
AU - Achkar, Christelle
AU - Barkovich, James
AU - Chelly, Jamel
AU - Engle, Elizabeth
AU - Hong, William
AU - Koh, Hyunyong
AU - Lassiter, Rhonda
AU - Marsh, Eric
AU - Pinsky, Rebecca
AU - Shain, Catherine
AU - Yuan, Bo
AU - Yuskaitis, Christopher
N1 - Publisher Copyright:
© 2022 American College of Medical Genetics and Genomics
PY - 2022/11
Y1 - 2022/11
N2 - Purpose: 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. Methods: 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. Results: 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. Conclusion: 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.
AB - Purpose: 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. Methods: 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. Results: 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. Conclusion: 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.
KW - AKT3
KW - MTOR
KW - PIK3CA
KW - PIK3R2
KW - Somatic mosaicism
UR - http://www.scopus.com/inward/record.url?scp=85136305405&partnerID=8YFLogxK
U2 - 10.1016/j.gim.2022.07.020
DO - 10.1016/j.gim.2022.07.020
M3 - Article
C2 - 35997716
AN - SCOPUS:85136305405
SN - 1098-3600
VL - 24
SP - 2240
EP - 2248
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 11
ER -