ABSTRACT
Purpose
RAS genes (HRAS, KRAS, and NRAS) are commonly found to be mutated in cancers, and activating RAS variants are also found in disorders of somatic mosaicism (DoSM). A survey of the
mutational spectrum of RAS variants in DoSM has not been performed.
Methods
A total of 938 individuals with suspected DoSM underwent high-sensitivity clinical
next-generation sequencing−based testing. We investigated the mutational spectrum
and genotype−phenotype associations of mosaic RAS variants.
Results
In this article, we present a series of individuals with DoSM with RAS variants. Classic hotspots, including Gly12, Gly13, and Gln61 constituted the majority
of RAS variants observed in DoSM. Furthermore, we present 12 individuals with HRAS and KRAS in-frame duplication/insertion (dup/ins) variants in the switch II domain. Among
the 18.3% individuals with RAS in-frame dup/ins variants, clinical findings were mainly associated with vascular
malformations. Hotspots were associated with a broad phenotypic spectrum, including
vascular tumors, vascular malformations, nevoid proliferations, segmental overgrowth,
digital anomalies, and combinations of these. The median age at testing was higher
and the variant allelic fraction was lower in individuals with in-frame dup/ins variants
than those in individuals with mosaic RAS hotspots.
Conclusion
Our work provides insight into the allelic and clinical heterogeneity of mosaic RAS variants in nonmalignant conditions.
Keywords
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Article info
Publication history
Published online: November 29, 2022
Accepted:
November 20,
2022
Received in revised form:
November 14,
2022
Received:
July 1,
2022
Identification
Copyright
© 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
