VCV000013983.14 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(26)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

Oncogenicity

The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate oncogenicity classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Oncogenic

criteria provided, single submitter

Variant Details

Identifiers

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

Variation ID: 13983 Accession: VCV000013983.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q32.33 14: 104780214 (GRCh38) [ NCBI UCSC ] 14: 105246551 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Feb 14, 2024	Oct 31, 2023
Somatic - Oncogenicity	Aug 11, 2024	Aug 11, 2024	Jul 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001382430.1:c.49G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001369359.1:p.Glu17Lys	missense
NM_001014431.2:c.49G>A	NP_001014431.1:p.Glu17Lys	missense
NM_001014432.2:c.49G>A	NP_001014432.1:p.Glu17Lys	missense
NM_001382431.1:c.49G>A	NP_001369360.1:p.Glu17Lys	missense
NM_001382432.1:c.49G>A	NP_001369361.1:p.Glu17Lys	missense
NM_001382433.1:c.49G>A	NP_001369362.1:p.Glu17Lys	missense
NM_005163.2:c.49G>A	NP_005154.2:p.Glu17Lys	missense
NC_000014.9:g.104780214C>T
NC_000014.8:g.105246551C>T
NG_012188.1:g.20531G>A
LRG_721:g.20531G>A
LRG_721t2:c.49G>A	LRG_721p2:p.Glu17Lys
	P31749:p.Glu17Lys

... more HGVS ... less HGVS

Protein change

E17K

Other names

Canonical SPDI

NC_000014.9:104780213:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Links

ClinGen: CA123660 UniProtKB: P31749#VAR_055422 OMIM: 164730.0001 dbSNP: rs121434592 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
AKT1		No evidence available	No evidence available	GRCh38 GRCh37	781	852

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Breast adenocarcinoma	Pathogenic (1)	no assertion criteria provided	Aug 18, 2011	RCV000015017.4
Carcinoma of colon	Pathogenic (1)	no assertion criteria provided	Aug 18, 2011	RCV000015018.4
Ovarian neoplasm	Pathogenic (1)	no assertion criteria provided	Aug 18, 2011	RCV000015019.4
Proteus syndrome	Pathogenic (3)	criteria provided, single submitter	Oct 31, 2023	RCV000031926.9
Thyroid tumor	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000421009.1
Bone osteosarcoma	Likely pathogenic (1)	no assertion criteria provided	Jul 14, 2015	RCV000421696.1
Endometrial Endometrioid Adenocarcinoma, Variant with Squamous Differentiation	Likely pathogenic (1)	no assertion criteria provided	Jul 14, 2015	RCV000431237.1
Lung adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000431723.1
Breast neoplasm	Pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000430173.1
Prostate adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000419412.1
Non-small cell lung carcinoma	Pathogenic (1)	no assertion criteria provided	Jul 14, 2015	RCV000436698.2
Neoplasm of uterine cervix	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000438154.1
Small cell lung carcinoma	Likely pathogenic (1)	no assertion criteria provided	Jul 14, 2015	RCV000421850.1
Squamous cell lung carcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000440828.1
Gastric adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000427484.1
Transitional cell carcinoma of the bladder	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000443761.1
Hepatocellular carcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000444311.1
Malignant melanoma of skin	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000426386.1
Neoplasm of the large intestine	Pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000429060.2
Squamous cell carcinoma of the head and neck	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000439982.1
Tumor of meninges	Likely pathogenic (1)	no assertion criteria provided	Jul 14, 2015	RCV000434120.1
Prostate neoplasm	Likely pathogenic (1)	no assertion criteria provided	Jul 14, 2015	RCV000445271.1
Cowden syndrome 6	Pathogenic (1)	criteria provided, single submitter	Jan 2, 2022	RCV000795313.7
not provided	Pathogenic (1)	criteria provided, single submitter	Jan 6, 2022	RCV001813745.2
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jan 06, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002061056.2 First in ClinVar: Jan 22, 2022 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Oct 31, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Proteus syndrome Affected status: yes Allele origin: somatic	Clinical Genomics Laboratory, Washington University in St. Louis Accession: SCV004176945.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: 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 … (more) 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. (less)
Pathogenic (Jan 02, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cowden syndrome 6 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000934768.4 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 17611497‚ 18954143‚ 21793738‚ 23237847 Comment: 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, … (more) 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). (less)
Pathogenic (Aug 18, 2011)	no assertion criteria provided Method: literature only	BREAST CANCER, SOMATIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV000035273.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (2) PubMed: 17611497‚ 21793738 Comment on evidence: Carpten et al. (2007) identified a 49G-A transition in the AKT1 gene, resulting in a glu17-to-lys (E17K) substitution, in tumor specimens from 5 of 61 … (more) Carpten et al. (2007) identified a 49G-A transition in the AKT1 gene, resulting in a glu17-to-lys (E17K) substitution, in tumor specimens from 5 of 61 (8%) breast cancer (114480) samples, 3 of 51 (6%) colorectal cancers (114500), and 1 of 50 (2%) ovarian cancers (167000). DNA from normal adjacent tissue or white blood cells showed no evidence of this mutation, which occurs in the PHD domain of AKT1. The AKT1 mutation was mutually exclusive with respect to mutations in PIK3CA (171834) and complete loss of PTEN (601728) protein expression. Carpten et al. (2007) showed that this mutation alters the AKT1-PHD conformation, results in activation of AKT1, and alters the subcellular location of AKT1 to the plasma membrane. Furthermore, Carpten et al. (2007) found that the AKT1 containing the E17K mutation was able to transform cells in culture and induce leukemia in mice. Lindhurst et al. (2011) performed exome sequencing of 11 DNA samples from 6 patients with Proteus syndrome (176920), as well as 1 sample each from 5 unaffected parents and from 1 patient's unaffected identical twin sib, and identified an activating E17K mutation in the AKT1 gene in 7 samples from 3 patients. The association was confirmed using a custom restriction-enzyme assay: overall, 26 (90%) of 29 patients with Proteus syndrome who were tested carried the E17K mutation in one or more samples, with the fraction of mutant DNA in the positive specimens ranging from 1% to approximately 50%. Mutant cell lines demonstrated greater AKT phosphorylation than control cell lines, and single-cell clones established from the same starting culture but differing in mutation status had different levels of AKT phosphorylation. (less)
Pathogenic (Aug 18, 2011)	no assertion criteria provided Method: literature only	OVARIAN CANCER, SOMATIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV000035275.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (2) PubMed: 17611497‚ 21793738 Comment on evidence: Carpten et al. (2007) identified a 49G-A transition in the AKT1 gene, resulting in a glu17-to-lys (E17K) substitution, in tumor specimens from 5 of 61 … (more) Carpten et al. (2007) identified a 49G-A transition in the AKT1 gene, resulting in a glu17-to-lys (E17K) substitution, in tumor specimens from 5 of 61 (8%) breast cancer (114480) samples, 3 of 51 (6%) colorectal cancers (114500), and 1 of 50 (2%) ovarian cancers (167000). DNA from normal adjacent tissue or white blood cells showed no evidence of this mutation, which occurs in the PHD domain of AKT1. The AKT1 mutation was mutually exclusive with respect to mutations in PIK3CA (171834) and complete loss of PTEN (601728) protein expression. Carpten et al. (2007) showed that this mutation alters the AKT1-PHD conformation, results in activation of AKT1, and alters the subcellular location of AKT1 to the plasma membrane. Furthermore, Carpten et al. (2007) found that the AKT1 containing the E17K mutation was able to transform cells in culture and induce leukemia in mice. Lindhurst et al. (2011) performed exome sequencing of 11 DNA samples from 6 patients with Proteus syndrome (176920), as well as 1 sample each from 5 unaffected parents and from 1 patient's unaffected identical twin sib, and identified an activating E17K mutation in the AKT1 gene in 7 samples from 3 patients. The association was confirmed using a custom restriction-enzyme assay: overall, 26 (90%) of 29 patients with Proteus syndrome who were tested carried the E17K mutation in one or more samples, with the fraction of mutant DNA in the positive specimens ranging from 1% to approximately 50%. Mutant cell lines demonstrated greater AKT phosphorylation than control cell lines, and single-cell clones established from the same starting culture but differing in mutation status had different levels of AKT phosphorylation. (less)
Pathogenic (Aug 18, 2011)	no assertion criteria provided Method: literature only	COLORECTAL CANCER, SOMATIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV000035274.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (2) PubMed: 17611497‚ 21793738 Comment on evidence: Carpten et al. (2007) identified a 49G-A transition in the AKT1 gene, resulting in a glu17-to-lys (E17K) substitution, in tumor specimens from 5 of 61 … (more) Carpten et al. (2007) identified a 49G-A transition in the AKT1 gene, resulting in a glu17-to-lys (E17K) substitution, in tumor specimens from 5 of 61 (8%) breast cancer (114480) samples, 3 of 51 (6%) colorectal cancers (114500), and 1 of 50 (2%) ovarian cancers (167000). DNA from normal adjacent tissue or white blood cells showed no evidence of this mutation, which occurs in the PHD domain of AKT1. The AKT1 mutation was mutually exclusive with respect to mutations in PIK3CA (171834) and complete loss of PTEN (601728) protein expression. Carpten et al. (2007) showed that this mutation alters the AKT1-PHD conformation, results in activation of AKT1, and alters the subcellular location of AKT1 to the plasma membrane. Furthermore, Carpten et al. (2007) found that the AKT1 containing the E17K mutation was able to transform cells in culture and induce leukemia in mice. Lindhurst et al. (2011) performed exome sequencing of 11 DNA samples from 6 patients with Proteus syndrome (176920), as well as 1 sample each from 5 unaffected parents and from 1 patient's unaffected identical twin sib, and identified an activating E17K mutation in the AKT1 gene in 7 samples from 3 patients. The association was confirmed using a custom restriction-enzyme assay: overall, 26 (90%) of 29 patients with Proteus syndrome who were tested carried the E17K mutation in one or more samples, with the fraction of mutant DNA in the positive specimens ranging from 1% to approximately 50%. Mutant cell lines demonstrated greater AKT phosphorylation than control cell lines, and single-cell clones established from the same starting culture but differing in mutation status had different levels of AKT phosphorylation. (less)
Pathogenic (Aug 18, 2011)	no assertion criteria provided Method: literature only	PROTEUS SYNDROME, SOMATIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV000043964.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (2) PubMed: 17611497‚ 21793738 Comment on evidence: Carpten et al. (2007) identified a 49G-A transition in the AKT1 gene, resulting in a glu17-to-lys (E17K) substitution, in tumor specimens from 5 of 61 … (more) Carpten et al. (2007) identified a 49G-A transition in the AKT1 gene, resulting in a glu17-to-lys (E17K) substitution, in tumor specimens from 5 of 61 (8%) breast cancer (114480) samples, 3 of 51 (6%) colorectal cancers (114500), and 1 of 50 (2%) ovarian cancers (167000). DNA from normal adjacent tissue or white blood cells showed no evidence of this mutation, which occurs in the PHD domain of AKT1. The AKT1 mutation was mutually exclusive with respect to mutations in PIK3CA (171834) and complete loss of PTEN (601728) protein expression. Carpten et al. (2007) showed that this mutation alters the AKT1-PHD conformation, results in activation of AKT1, and alters the subcellular location of AKT1 to the plasma membrane. Furthermore, Carpten et al. (2007) found that the AKT1 containing the E17K mutation was able to transform cells in culture and induce leukemia in mice. Lindhurst et al. (2011) performed exome sequencing of 11 DNA samples from 6 patients with Proteus syndrome (176920), as well as 1 sample each from 5 unaffected parents and from 1 patient's unaffected identical twin sib, and identified an activating E17K mutation in the AKT1 gene in 7 samples from 3 patients. The association was confirmed using a custom restriction-enzyme assay: overall, 26 (90%) of 29 patients with Proteus syndrome who were tested carried the E17K mutation in one or more samples, with the fraction of mutant DNA in the positive specimens ranging from 1% to approximately 50%. Mutant cell lines demonstrated greater AKT phosphorylation than control cell lines, and single-cell clones established from the same starting culture but differing in mutation status had different levels of AKT phosphorylation. (less)
Pathogenic (Jul 14, 2015)	no assertion criteria provided Method: literature only	Non-small cell lung carcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504511.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (6) PubMed: 18256540‚ 23728071‚ 18611285‚ 17611497‚ 25157968‚ 18504432 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000349310:c.49G>A
Likely pathogenic (Jul 14, 2015)	no assertion criteria provided Method: literature only	Endometrial Endometrioid Adenocarcinoma, Variant with Squamous Differentiation (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504510.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (2) PubMed: 25157968‚ 19853286 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000349310:c.49G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Prostate adenocarcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504512.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000349310:c.49G>A
Pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Breast neoplasm (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504513.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (11) PubMed: 19487299‚ 17611497‚ 19418217‚ 21512767‚ 25157968‚ 26619011‚ 21464312‚ 22538770‚ 20453058‚ 23237847‚ 22722201 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000349310:c.49G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Squamous cell lung carcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504514.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000349310:c.49G>A
Likely pathogenic (Jul 14, 2015)	no assertion criteria provided Method: literature only	Small cell lung carcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504515.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (2) PubMed: 25157968‚ 24657128 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000349310:c.49G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	None (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504517.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000349310:c.49G>A
Pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Neoplasm of the large intestine (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504516.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (7) PubMed: 18392055‚ 23934607‚ 26619011‚ 23700467‚ 20233444‚ 25157968‚ 17611497 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000349310:c.49G>A
Likely pathogenic (Jul 14, 2015)	no assertion criteria provided Method: literature only	Osteosarcoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504521.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (2) PubMed: 25157968‚ 24190505 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000349310:c.49G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Thyroid tumor (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504518.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000349310:c.49G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	None (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504519.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (3) PubMed: 26619011‚ 22980975‚ 25157968 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000349310:c.49G>A
Likely pathogenic (Jul 14, 2015)	no assertion criteria provided Method: literature only	Prostate neoplasm (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504520.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (3) PubMed: 22610119‚ 25157968‚ 22722839 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000349310:c.49G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Hepatocellular carcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504523.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000349310:c.49G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Gastric adenocarcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504524.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000349310:c.49G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Neoplasm of uterine cervix (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504525.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000349310:c.49G>A
Likely pathogenic (Jul 14, 2015)	no assertion criteria provided Method: literature only	Tumor of meninges (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504522.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (2) PubMed: 25157968‚ 23348505 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000349310:c.49G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Malignant melanoma of skin (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504527.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000349310:c.49G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Transitional cell carcinoma of the bladder (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504526.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000349310:c.49G>A
not provided (-)	no classification provided Method: literature only	Proteus syndrome Affected status: unknown Allele origin: somatic	GeneReviews Accession: SCV000054577.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: BookShelf: NBK99495 BookShelf: NBK99495
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Comment:

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)

Comment:

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.

Comment:

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).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Proteus Syndrome.	Adam MP	-	2023	PMID: 22876373
Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.	Chang MT	Nature biotechnology	2016	PMID: 26619011
Prospective enterprise-level molecular genotyping of a cohort of cancer patients.	MacConaill LE	The Journal of molecular diagnostics : JMD	2014	PMID: 25157968
Molecular profiling of small cell lung cancer in a Japanese cohort.	Wakuda K	Lung cancer (Amsterdam, Netherlands)	2014	PMID: 24657128
Exomic analysis of myxoid liposarcomas, synovial sarcomas, and osteosarcomas.	Joseph CG	Genes, chromosomes & cancer	2014	PMID: 24190505
Alterations in the EGFR pathway coincide in colorectal cancer and impact on prognosis.	Neumann J	Virchows Archiv : an international journal of pathology	2013	PMID: 23934607
A detailed immunohistochemical analysis of the PI3K/AKT/mTOR pathway in lung cancer: correlation with PIK3CA, AKT1, K-RAS or PTEN mutational status and clinicopathological features.	Trigka EA	Oncology reports	2013	PMID: 23728071
Targeted sequencing of cancer-related genes in colorectal cancer using next-generation sequencing.	Han SW	PloS one	2013	PMID: 23700467
Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.	Clark VE	Science (New York, N.Y.)	2013	PMID: 23348505
Functional analysis of non-hotspot AKT1 mutants found in human breast cancers identifies novel driver mutations: implications for personalized medicine.	Yi KH	Oncotarget	2013	PMID: 23237847
Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing.	Imielinski M	Cell	2012	PMID: 22980975
The mutational landscape of lethal castration-resistant prostate cancer.	Grasso CS	Nature	2012	PMID: 22722839
The landscape of cancer genes and mutational processes in breast cancer.	Stephens PJ	Nature	2012	PMID: 22722201
Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer.	Barbieri CE	Nature genetics	2012	PMID: 22610119
Mutation profiling identifies numerous rare drug targets and distinct mutation patterns in different clinical subtypes of breast cancers.	Santarpia L	Breast cancer research and treatment	2012	PMID: 22538770
Mutational characterization of individual breast tumors: TP53 and PI3K pathway genes are frequently and distinctively mutated in different subtypes.	Boyault S	Breast cancer research and treatment	2012	PMID: 21512767
A mosaic activating mutation in AKT1 associated with the Proteus syndrome.	Lindhurst MJ	The New England journal of medicine	2011	PMID: 21793738
Deactivation of Akt by a small molecule inhibitor targeting pleckstrin homology domain and facilitating Akt ubiquitination.	Jo H	Proceedings of the National Academy of Sciences of the United States of America	2011	PMID: 21464312
Predictive biomarkers of sensitivity to the phosphatidylinositol 3' kinase inhibitor GDC-0941 in breast cancer preclinical models.	O'Brien C	Clinical cancer research : an official journal of the American Association for Cancer Research	2010	PMID: 20453058
A rapid, sensitive, reproducible and cost-effective method for mutation profiling of colon cancer and metastatic lymph nodes.	Fumagalli D	BMC cancer	2010	PMID: 20233444
AKT1 pleckstrin homology domain E17K activating mutation in endometrial carcinoma.	Cohen Y	Gynecologic oncology	2010	PMID: 19853286
Phosphatidylinositol-3-kinase and AKT1 mutations occur early in breast carcinoma.	Dunlap J	Breast cancer research and treatment	2010	PMID: 19418217
Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1.	Ricarte-Filho JC	Cancer research	2009	PMID: 19487299
Molecular mechanism of an oncogenic mutation that alters membrane targeting: Glu17Lys modifies the PIP lipid specificity of the AKT1 PH domain.	Landgraf KE	Biochemistry	2008	PMID: 18954143
Detection of the transforming AKT1 mutation E17K in non-small cell lung cancer by high resolution melting.	Do H	BMC research notes	2008	PMID: 18611285
AKT1(E17K) in human solid tumours.	Bleeker FE	Oncogene	2008	PMID: 18504432
Mutational analysis of oncogenic AKT E17K mutation in common solid cancers and acute leukaemias.	Kim MS	British journal of cancer	2008	PMID: 18392055
Activating E17K mutation in the gene encoding the protein kinase AKT1 in a subset of squamous cell carcinoma of the lung.	Malanga D	Cell cycle (Georgetown, Tex.)	2008	PMID: 18256540
A transforming mutation in the pleckstrin homology domain of AKT1 in cancer.	Carpten JD	Nature	2007	PMID: 17611497
http://docm.genome.wustl.edu/variants/ENST00000349310:c.49G>A	-	-	-	-
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Conditions - Somatic

Tumor type Help The tumor type for this variant-condition (RCV) record in ClinVar.	Clinical impact (# of submissions) Help The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Oncogenicity Help The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the tumor type.	Variation/condition record Help The most recent date that a submitter evaluated this variant for the tumor type.
Neoplasm		Oncogenic criteria provided, single submitter	Jul 31, 2024	RCV004668732.1

Submissions - Somatic

Oncogenicity Help The submitted oncogenicity classification for each SCV record. (Last evaluated)	Review Status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Tumor type Help The tumor type for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.

Oncogenic

(Jul 31, 2024)

(ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022)

Method: clinical testing

Neoplasm

Affected status: unknown

Allele origin: somatic

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Accession: SCV005094330.1
First In ClinVar: Aug 11, 2024
Last updated: Aug 11, 2024

Comment:

Citations for somatic classification of this variant

There are no citations for somatic classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs121434592 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Conditions - Somatic

Submissions - Somatic

Citations for somatic classification of this variant

Text-mined citations for rs121434592 ...