14-104780214-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: 1483 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

Our verdict: Pathogenic. The variant received 12 points.

• PS3: 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)
• PM2: Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
• PM5: 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)
• PP5: 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	missense splice_region	Exon 4 of 15	NP_001369359.1	B0LPE5
	AKT1	NM_001014431.2		c.49G>A	p.Glu17Lys	missense splice_region	Exon 3 of 14	NP_001014431.1	B0LPE5
	AKT1	NM_001014432.2		c.49G>A	p.Glu17Lys	missense splice_region	Exon 4 of 15	NP_001014432.1	P31749-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT1	ENST00000649815.2	MANE Select	c.49G>A	p.Glu17Lys	missense splice_region	Exon 4 of 15	ENSP00000497822.1	P31749-1
	AKT1	ENST00000349310.7	TSL:1	c.49G>A	p.Glu17Lys	missense splice_region	Exon 4 of 15	ENSP00000270202.4	P31749-1
	AKT1	ENST00000402615.6	TSL:1	c.49G>A	p.Glu17Lys	missense splice_region	Exon 3 of 14	ENSP00000385326.2	P31749-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250006 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

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

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
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
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.037	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.92
gMVP		0.38
Mutation Taster		=43/57	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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.

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