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Pathogenic variants in the receptor tyrosine kinase TIE2, encoded by TEK, are known to cause vascular malformations (VMs). In this study, we retrospectively reviewed the deidentified data generated through clinical NGS testing in our laboratory and found 88 VM cases with a total of 107 clinically significant TEK variants. Among those, 23 unique variants at the amino acid level were identified, including five novel (p.Cys1040Arg, p.Arg1099PhefsTer12, p.Glu1109Ter, p.Phe1111LeufsTer7, p.Phe1111ValfsTer7) and 18 previously published variants. Missense variants were identified more often in the tyrosine kinase domain, while all nonsense/frameshift variants were clustered in the C-terminal tail (CTT). In addition, most variants occurred as solitary alterations, whereas certain variants always co-occurred with a second TEK variant. Five patterns of TEK variants (P1-P5) were identified: (P1) Arg849 + another variant; (P2) Tyr897 + another variant; (P3) Leu914 single variants; (P4) Arg915/918 single variants; and (P5) CTT single /co-occurring variants. This study provides the most comprehensive view of pathogenic TEK variants in VMs to date., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Disorders of somatic mosaicism (DoSMs) are rare genetic disorders arising from postzygotic alteration leading to segmental/nonsegmental disease. Current professional guidelines for standardized variant interpretation focus on germline and cancer variants, making them suboptimal for DoSM variant interpretation. The Brain Malformations Variant Curation Expert Panel (BMVCEP) modified existing guidelines to account for brain-specific disorders of somatic mosaicism, but applicability to other DoSM presentations is limited. At Washington University in St. Louis School of Medicine, we have adopted the BMVCEP interpretation framework but suggested alterations that make it more suitable for generalized DoSM variant classification. These modifications include (1) expanding applicability beyond genes associated with brain malformations, (2) introduction of a criterion to interpret truncating variants at the C-terminus of gain of function genes, (3) establishment of a variant allele fraction (VAF) cutoff for applying de novo criteria, and (4) demonstration that in silico prediction tools are relevant to interpretation of gain of function missense variants. Furthermore, modifications to BMVCEP guidelines reduce the number of variants classified as uncertain. The variant classification considerations that we propose have the potential to improve the accuracy of somatic variant classification, better inform clinical care, and may benefit clinical laboratories also conducting DoSM testing., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)