Total submissions: 26
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000795313 | SCV000934768 | pathogenic | Cowden syndrome 6 | 2022-01-02 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects AKT1 function (PMID: 17611497, 18954143, 21793738, 23237847). 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"). ClinVar contains an entry for this variant (Variation ID: 13983). This missense change has been observed in individuals with Proteus syndrome (PMID: 21793738). 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). |
Gene |
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, |
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 | Neoplasm of ovary | 2011-08-18 | no assertion criteria provided | literature only | |
OMIM | RCV000031926 | SCV000043964 | pathogenic | Proteus syndrome | 2011-08-18 | no assertion criteria provided | literature only | |
Gene |
RCV000031926 | SCV000054577 | not provided | Proteus syndrome | no assertion provided | literature only | ||
Database of Curated Mutations |
RCV000431237 | SCV000504510 | likely pathogenic | Endometrial Endometrioid Adenocarcinoma, Variant with Squamous Differentiation | 2015-07-14 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436698 | SCV000504511 | pathogenic | Non-small cell lung carcinoma | 2015-07-14 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419412 | SCV000504512 | likely pathogenic | Prostate adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000430173 | SCV000504513 | pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000440828 | SCV000504514 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000421850 | SCV000504515 | likely pathogenic | Small cell lung carcinoma | 2015-07-14 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000429060 | SCV000504516 | pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439982 | SCV000504517 | likely pathogenic | Squamous cell carcinoma of the head and neck | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000421009 | SCV000504518 | likely pathogenic | Thyroid tumor | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000431723 | SCV000504519 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000445271 | SCV000504520 | likely pathogenic | Prostate neoplasm | 2015-07-14 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000421696 | SCV000504521 | likely pathogenic | Bone osteosarcoma | 2015-07-14 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000434120 | SCV000504522 | likely pathogenic | Tumor of meninges | 2015-07-14 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444311 | SCV000504523 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427484 | SCV000504524 | likely pathogenic | Gastric adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000438154 | SCV000504525 | likely pathogenic | Neoplasm of uterine cervix | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000443761 | SCV000504526 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426386 | SCV000504527 | likely pathogenic | Malignant melanoma of skin | 2016-05-31 | no assertion criteria provided | literature only |