Submissions for variant NM_001382430.1(AKT1):c.49G>A (p.Glu17Lys)

dbSNP: rs121434592

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000795313	SCV000934768	pathogenic	Cowden syndrome 6	2022-01-02	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs121434592, gnomAD 0.0009%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 17 of the AKT1 protein (p.Glu17Lys). This missense change has been observed in individuals with Proteus syndrome (PMID: 21793738). ClinVar contains an entry for this variant (Variation ID: 13983). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects AKT1 function (PMID: 17611497, 18954143, 21793738, 23237847). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001813745	SCV002061056	pathogenic	not provided	2022-01-06	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that E17K is a gain-of-function variant, as E17K produced increased Akt1 activation and downstream signaling compared with wild type (Yi et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in biopsy samples of patients with Proteus syndrome (Lindhurst et al., 2011); This variant is associated with the following publications: (PMID: 30103035, 26872686, 29681107, 17611497, 21793738, 23237847, 18954143, 25782637, 32617723, 33442022, 33030203, 33303690)
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000031926	SCV004176945	pathogenic	Proteus syndrome	2023-10-31	criteria provided, single submitter	clinical testing	An AKT1 c.49G>A (p.Glu17Lys) variant was identified at an allelic fraction that is consistent with somatic origin. This variant has been reported in numerous individuals with Proteus syndrome (Lindhurst MJ et al., PMID: 21793738; Wee JS et al., PMID: 24850616; Pithadia DJ et al., PMID: 32035943; Schmidt J et al., PMID: 35670639; McNulty SN et al. PMID: 31585106) and in numerous types of cancer in the cancer database COSMIC (Genomic mutation ID: COSV62571334). It has been reported in the ClinVar database as a pathogenic variant by two submitters (ClinVar ID: 13983). The AKT1 c.49G>A (p.Glu17Lys) variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. It resides within a region, the pleckstrin homology domain, of AKT1 that is defined as a critical functional domain (Shoji K et al. PMID:19491896). Functional studies show that the AKT1 c.49G>A (p.Glu17Lys) variant significantly activates AKT1 phosphorylation and signaling in patient cell lines and animal models, indicating that this variant impacts protein function (Lindhurst MJ et al., PMID: 21793738; Blum N, Harris MP., PMID: 36621776). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868), the AKT1 c.49G>A (p.Glu17Lys) variant is classified as pathogenic.
OMIM	RCV000015017	SCV000035273	pathogenic	Breast adenocarcinoma	2011-08-18	no assertion criteria provided	literature only
OMIM	RCV000015018	SCV000035274	pathogenic	Carcinoma of colon	2011-08-18	no assertion criteria provided	literature only
OMIM	RCV000015019	SCV000035275	pathogenic	Ovarian neoplasm	2011-08-18	no assertion criteria provided	literature only
OMIM	RCV000031926	SCV000043964	pathogenic	Proteus syndrome	2011-08-18	no assertion criteria provided	literature only
GeneReviews	RCV000031926	SCV000054577	not provided	Proteus syndrome		no assertion provided	literature only