chr14-104780214-C-T

Variant names:

• chr14-104780214-C-T
• rs121434592
• NM_001382430.1:c.49G>A
• AKT1 p.Glu17Lys

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+12 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 12 classification points (ACMG Germline Pathogenicity v2019). PS3PM2PM5PP5_Strong

The NM_001382430.1(AKT1):c.49G>A (p.Glu17Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.81). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004176945: 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" and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.E17R: Pathogenic (ClinVar VariationId 800567, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.E17?: Uncertain_significance (ClinVar VariationId 1524334, 1 star) This exact variant is established as oncogenic in: ClinVar, CGI (Cancer Genome Interpreter). The variant position is a cancer hotspot (cancerhotspots.org): 149 samples carry this exact amino acid change out of 298 samples with a variant at this residue. This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AKT1 NM_001382430.1 missense, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:6
• Conservation: PhyloP100: 7.81
• Publications: 1 publications found

Genes affected

AKT1 (HGNC:391): (AKT serine/threonine kinase 1) This gene encodes one of the three members of the human AKT serine-threonine protein kinase family which are often referred to as protein kinase B alpha, beta, and gamma. These highly similar AKT proteins all have an N-terminal pleckstrin homology domain, a serine/threonine-specific kinase domain and a C-terminal regulatory domain. These proteins are phosphorylated by phosphoinositide 3-kinase (PI3K). AKT/PI3K forms a key component of many signalling pathways that involve the binding of membrane-bound ligands such as receptor tyrosine kinases, G-protein coupled receptors, and integrin-linked kinase. These AKT proteins therefore regulate a wide variety of cellular functions including cell proliferation, survival, metabolism, and angiogenesis in both normal and malignant cells. AKT proteins are recruited to the cell membrane by phosphatidylinositol 3,4,5-trisphosphate (PIP3) after phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) by PI3K. Subsequent phosphorylation of both threonine residue 308 and serine residue 473 is required for full activation of the AKT1 protein encoded by this gene. Phosphorylation of additional residues also occurs, for example, in response to insulin growth factor-1 and epidermal growth factor. Protein phosphatases act as negative regulators of AKT proteins by dephosphorylating AKT or PIP3. The PI3K/AKT signalling pathway is crucial for tumor cell survival. Survival factors can suppress apoptosis in a transcription-independent manner by activating AKT1 which then phosphorylates and inactivates components of the apoptotic machinery. AKT proteins also participate in the mammalian target of rapamycin (mTOR) signalling pathway which controls the assembly of the eukaryotic translation initiation factor 4F (eIF4E) complex and this pathway, in addition to responding to extracellular signals from growth factors and cytokines, is disregulated in many cancers. Mutations in this gene are associated with multiple types of cancer and excessive tissue growth including Proteus syndrome and Cowden syndrome 6, and breast, colorectal, and ovarian cancers. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2020]

AKT1 Gene-Disease associations (from GenCC):

• Proteus syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden syndrome 6

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV004176945: 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).; SCV000934768: Experimental studies have shown that this missense change affects AKT1 function (PMID: 17611497, 18954143, 21793738, 23237847).; SCV002061056: Published functional studies demonstrate a gain-of-function effect, as E17K produced increased Akt1 activation and downstream signaling compared to wild type (PMID: 21793738, 23237847)
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.E17R: Pathogenic (ClinVar VariationId 800567, 1 star); Other variants at the same amino acid residue (not pathogenic): p.E17?: Uncertain_significance (ClinVar VariationId 1524334, 1 star)
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001382430.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	AKT1 NM_001382430.1	MANE Select	c.49G>A p.Glu17Lys	missensesplice_region	Exon 4 of 15	Prot: NP_001369359.1 UniProt:
	AKT1 NM_001014431.2		c.49G>A p.Glu17Lys	missensesplice_region	Exon 3 of 14	Prot: NP_001014431.1 UniProt:
	AKT1 NM_001014432.2		c.49G>A p.Glu17Lys	missensesplice_region	Exon 4 of 15	Prot: NP_001014432.1 UniProt:

AKT1 NM_001382430.1

MANE Select

HGVSc / HGVSpc.49G>Ap.Glu17Lys

Exon rankExon 4 of 15

missensesplice_region

Prot: NP_001369359.1UniProt: P31749-1B0LPE5

AKT1 NM_001014431.2

HGVSc / HGVSpc.49G>Ap.Glu17Lys

Exon rankExon 3 of 14

missensesplice_region

Prot: NP_001014431.1UniProt: B0LPE5P31749-1

AKT1 NM_001014432.2

HGVSc / HGVSpc.49G>Ap.Glu17Lys

Exon rankExon 4 of 15

missensesplice_region

Prot: NP_001014432.1UniProt: P31749-1B0LPE5

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	AKT1 ENST00000649815.2	MANE Select	c.49G>A p.Glu17Lys	missensesplice_region	Exon 4 of 15	Prot: ENSP00000497822.1 UniProt:
	AKT1 ENST00000349310.7	TSL:1	c.49G>A p.Glu17Lys	missensesplice_region	Exon 4 of 15	Prot: ENSP00000270202.4 UniProt:
	AKT1 ENST00000402615.6	TSL:1	c.49G>A p.Glu17Lys	missensesplice_region	Exon 3 of 14	Prot: ENSP00000385326.2 UniProt:

AKT1 ENST00000649815.2

MANE Select

HGVSc / HGVSpc.49G>Ap.Glu17Lys

Exon rankExon 4 of 15

missensesplice_region

Prot: ENSP00000497822.1UniProt: P31749-1

AKT1 ENST00000349310.7

TSL:1

HGVSc / HGVSpc.49G>Ap.Glu17Lys

Exon rankExon 4 of 15

missensesplice_region

Prot: ENSP00000270202.4UniProt: P31749-1

AKT1 ENST00000402615.6

TSL:1

HGVSc / HGVSpc.49G>Ap.Glu17Lys

Exon rankExon 3 of 14

missensesplice_region

Prot: ENSP00000385326.2UniProt: P31749-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD2 exomes	AF: 0.00000400	AC:1	Hom:	AN:250006	Cov:
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:2300	Cov:

Showing 5 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Proteus syndrome (4)
1	-	-	Breast adenocarcinoma (1)
1	-	-	Carcinoma of colon (1)
1	-	-	Cowden syndrome 6 (1)
1	-	-	not provided (1)
1	-	-	Ovarian neoplasm (1)
-	-	-	Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype (1)
-	-	-	Medulloblastoma SHH activated and TP53 wild-type (1)
-	-	-	Meningioma (2)
-	-	-	Neoplasm (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	34
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	1.0	D
FuncVEP CTI	Pathogenic	1.0
GPN-Star LLR	N/A	-9.5
GPN-Star score	N/A	9.5
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.64	T
Mutation Taster	N/A	43/57	disease causing (ClinVar)
MutationAssessor	Uncertain	2.5	M
PhyloP100	Pathogenic	7.8
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.7	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1
REVEL	Uncertain	0.51
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.037	D
Varity_R	N/A	0.92
VESM-3B	Benign	-12

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.050
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs121434592;

hg19: chr14-105246551;

COSMIC: COSV62571334;

COSMIC: COSV62571334;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar