14-104780214-C-A

Variant names:

• chr14-104780214-C-A
• rs121434592
• NM_001382430.1:c.49G>T
• AKT1 p.Glu17*

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_001382430.1(AKT1):c.49G>T (p.Glu17*) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.81). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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 stop_gained, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.81
• Publications: 1309 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: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	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.

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>T p.Glu17*	stop_gainedsplice_region	Exon 4 of 15	Prot: NP_001369359.1 UniProt:
	AKT1 NM_001014431.2		c.49G>T p.Glu17*	stop_gainedsplice_region	Exon 3 of 14	Prot: NP_001014431.1 UniProt:
	AKT1 NM_001014432.2		c.49G>T p.Glu17*	stop_gainedsplice_region	Exon 4 of 15	Prot: NP_001014432.1 UniProt:

AKT1 NM_001382430.1

MANE Select

HGVSc / HGVSpc.49G>Tp.Glu17*

Exon rankExon 4 of 15

stop_gainedsplice_region

Prot: NP_001369359.1UniProt: P31749-1B0LPE5

AKT1 NM_001014431.2

HGVSc / HGVSpc.49G>Tp.Glu17*

Exon rankExon 3 of 14

stop_gainedsplice_region

Prot: NP_001014431.1UniProt: B0LPE5P31749-1

AKT1 NM_001014432.2

HGVSc / HGVSpc.49G>Tp.Glu17*

Exon rankExon 4 of 15

stop_gainedsplice_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>T p.Glu17*	stop_gainedsplice_region	Exon 4 of 15	Prot: ENSP00000497822.1 UniProt:
	AKT1 ENST00000349310.7	TSL:1	c.49G>T p.Glu17*	stop_gainedsplice_region	Exon 4 of 15	Prot: ENSP00000270202.4 UniProt:
	AKT1 ENST00000402615.6	TSL:1	c.49G>T p.Glu17*	stop_gainedsplice_region	Exon 3 of 14	Prot: ENSP00000385326.2 UniProt:

AKT1 ENST00000649815.2

MANE Select

HGVSc / HGVSpc.49G>Tp.Glu17*

Exon rankExon 4 of 15

stop_gainedsplice_region

Prot: ENSP00000497822.1UniProt: P31749-1

AKT1 ENST00000349310.7

TSL:1

HGVSc / HGVSpc.49G>Tp.Glu17*

Exon rankExon 4 of 15

stop_gainedsplice_region

Prot: ENSP00000270202.4UniProt: P31749-1

AKT1 ENST00000402615.6

TSL:1

HGVSc / HGVSpc.49G>Tp.Glu17*

Exon rankExon 3 of 14

stop_gainedsplice_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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	47
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	52
DANN	Uncertain	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	1.0	D
GPN-Star LLR	N/A	-11
GPN-Star score	N/A	11
Mutation Taster	N/A	6/194	disease causing (fs/PTC)
PhyloP100	Pathogenic	7.8
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1

Showing 14 of 14 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
DS_AG_spliceai	Uncertain	0.26	Position offset: -3
Pangolin (max)	Uncertain	0.22
Pangolin gain	Uncertain	0.22	Position offset: -3
SpliceAI score (max)	Uncertain	0.26	Details are displayed if max score is > 0.2

Showing 4 of 4 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: COSV62576849;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar