Submissions for variant NM_004985.5(KRAS):c.197_223dup (p.Ala66_Thr74dup)

dbSNP: rs2141509708

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV001533002	SCV001745389	likely pathogenic	Venous malformation	2021-07-06	criteria provided, single submitter	clinical testing	A likely pathogenic variant was identified in exon 3 of KRAS (NM_004985.4:c.197_223dup, p.Ala66_Thr74dup). This variant was identified in ~1% of reads (depth of coverage =2,343x), consistent with somatic origin. This variant is not reported in the medical literature, control population database (gnomAD).   KRAS is a GTPase that functions as an upstream regulator of the MAPK and PI3K pathways. The duplication of 27 nucleotides causes an inframe insertion of 9 amino acids. This alteration occurs within the "switch II" domain of the KRAS protein that is highly conserved across species. Different insertion mutations within this domain have been reported to disrupt GTP hydrolysis and result in constitutive KRAS activation. The functional effect of p.Ala66_Thr74dup has not been experimentally tested.   Although this particular mutation has not been previously reported, a similar variant (KRAS p.Ser65_Ala66insAspSer) has been reported in a 10 year old patient with an arteriovenous malformation of the left parietal lobe (PMID: 30544177). Similarly, a patient with a probable arteriovenous malformation was reported to have a mosaic KRAS p.Glu63_Asp69dup variant (PMID: 31160609).   Mosaic activating variants in KRAS have been previously reported in several unrelated individuals with a spectrum of clinical features, including isolated arteriovenous malformations.