AKT1c.49G>ALikely pathogenic

Print report

Variant interpretation report

AKT1 c.49G>A, p.(Glu17Lys)

NM_001014431.1:c.49G>A NP_001014431.1:p.(Glu17Lys) View identifiers

Classification

Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About AKT1

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 strong (pathogenic) · 1 moderate (pathogenic) · 2 supporting (pathogenic)
Expert rules: Not recorded
Other laboratories (ClinVar): 4 Pathogenic
Pipeline record: 16 Jun 2026

Evidence considered

View criteria

Applied evidence criteria

PS3 (strong): Well-established functional studies in multiple publications demonstrate that the E17K substitution results in constitutive activation of AKT1 kinase, increased AKT phosphorylation (pT308, pS473), altered lipid-binding specificity in the PH domain, growth factor-independent survival in BaF3 cells, anchorage-independent growth in NIH 3T3 cells, disruption of 3D acinar morphogenesis in MCF10A cells, and oncogenesis in murine models. The PH-KD autoinhibitory interaction is weakened by E17K, providing a structural mechanistic basis. Multiple independent assays across multiple laboratories confirm a gain-of-function effect.
PM1 (moderate): The variant resides at codon 17 within the pleckstrin homology (PH) domain of AKT1 (residues ~5-108), a critical functional domain essential for membrane localization, autoinhibition, and kinase regulation. The PH domain is a well-established mutational hotspot where pathogenic gain-of-function missense variants cluster and benign missense variation is notably absent. This variant lies in a statistically significant hotspot per the hotspots analysis. Multiple structural and functional studies (PMID:17611497, PMID:23134728) confirm that missense variants in the PH domain are overwhelmingly pathogenic.
PM2 (supporting): The variant is present in gnomAD v2.1 at an extremely low allele frequency (AF = 3.9999 × 10⁻⁶; 1/250,006 alleles; 0.0004%) and is absent from gnomAD v4.1. This frequency is well below the PM2 threshold of <0.1%, meeting the criterion for absent or extremely rare in population databases. The single observation in gnomAD v2.1 is in the European (non-Finnish) subpopulation (AF = 8.87 × 10⁻⁶).
PP5 (supporting): ClinVar reports this variant as Pathogenic by 4 clinical laboratories (including Labcorp Genetics/Invitae and Variantyx), with review status 'criteria provided, single submitter'. Under generic ACMG/AMP, PP5 can be applied when a reputable clinical laboratory classifies the variant as pathogenic. Although the review status indicates only one submitter provided classification criteria, the concordance across 4 clinical laboratories supports application of PP5 at supporting strength.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 4 Benign evidence criteria: 0

Pathogenic criteria applied · 4

PS3Strong

PS3 · strong

Well-established functional studies in multiple publications demonstrate that the E17K substitution results in constitutive activation of AKT1 kinase, increased AKT phosphorylation (pT308, pS473), altered lipid-binding specificity in the PH domain, growth factor-independent survival in BaF3 cells, anchorage-independent growth in NIH 3T3 cells, disruption of 3D acinar morphogenesis in MCF10A cells, and oncogenesis in murine models. The PH-KD autoinhibitory interaction is weakened by E17K, providing a structural mechanistic basis. Multiple independent assays across multiple laboratories confirm a gain-of-function effect.

PM1Moderate

PM1 · moderate

The variant resides at codon 17 within the pleckstrin homology (PH) domain of AKT1 (residues ~5-108), a critical functional domain essential for membrane localization, autoinhibition, and kinase regulation. The PH domain is a well-established mutational hotspot where pathogenic gain-of-function missense variants cluster and benign missense variation is notably absent. This variant lies in a statistically significant hotspot per the hotspots analysis. Multiple structural and functional studies (PMID:17611497, PMID:23134728) confirm that missense variants in the PH domain are overwhelmingly pathogenic.

PM2Supporting

PM2 · supporting

The variant is present in gnomAD v2.1 at an extremely low allele frequency (AF = 3.9999 × 10⁻⁶; 1/250,006 alleles; 0.0004%) and is absent from gnomAD v4.1. This frequency is well below the PM2 threshold of <0.1%, meeting the criterion for absent or extremely rare in population databases. The single observation in gnomAD v2.1 is in the European (non-Finnish) subpopulation (AF = 8.87 × 10⁻⁶).

PP5Supporting

PP5 · supporting

ClinVar reports this variant as Pathogenic by 4 clinical laboratories (including Labcorp Genetics/Invitae and Variantyx), with review status 'criteria provided, single submitter'. Under generic ACMG/AMP, PP5 can be applied when a reputable clinical laboratory classifies the variant as pathogenic. Although the review status indicates only one submitter provided classification criteria, the concordance across 4 clinical laboratories supports application of PP5 at supporting strength.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 strong, PM1 moderate, PM2 supporting, PP5 supporting; combination = 1 strong + 1 moderate + 2 supporting, which maps to Likely Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.9999e-06; MAF= 0.00040%, 1/250006 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.87185e-06; MAF= 0.00089%, 1/112716 alleles, homozygotes = 0).

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

4 reported laboratory submissions

4 Pathogenic.

Applied · PP5 → ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.

Applied · PS3 → OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

894 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV62571334, n = 894 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 4 met · 8 not met · 9 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

The AKT1 c.49G>A (p.Glu17Lys) variant resides in the pleckstrin homology (PH) domain, a critical functional domain, and lies within a statistically significant mutational hotspot where benign missense variation is notably absent (PM1_Moderate).

This variant is present in gnomAD v2.1 at an extremely low allele frequency of 0.0004% (1/250,006 alleles) and is absent from gnomAD v4.1, meeting the PM2 threshold for absence from population databases (PM2_Supporting).

Well-established functional studies from multiple independent laboratories demonstrate that the E17K substitution results in constitutive AKT1 kinase activation, altered lipid-binding specificity, enhanced downstream signaling, transformation in cell-based assays, and oncogenesis in murine models (PS3_Strong).

ClinVar reports this variant as Pathogenic by 4 clinical laboratories including Labcorp Genetics/Invitae and Variantyx (PP5_Supporting).

The computational in silico predictors are equivocal (REVEL 0.51, BayesDel 0.116); PP3 is not met. BS3 is contradicted by overwhelming functional evidence of a damaging gain-of-function effect. BA1 and BS1 are not met given the extremely low population frequency.

Under the generic ACMG/AMP 2015 framework (PMID:25741868), the criteria met are: PS3_Strong + PM1_Moderate + PM2_Supporting + PP5_Supporting. This combination (1 Strong + 1 Moderate + 2 Supporting) meets the threshold for Likely Pathogenic per Richards et al. 2015 (1 Strong AND ≥1 Moderate AND ≥2 Supporting qualifies as Likely Pathogenic).

Met · 4

PS3 StrongWell-established functional studies in multiple publications demonstrate that the E17K substitution results in constitutive activation of AKT1 kinase, increased AKT phosphorylation (pT308, pS473), altered lipid-binding specificity in the PH domain, growth factor-independent survival in BaF3 cells, anchorage-independent growth in NIH 3T3 cells, disruption of 3D acinar morphogenesis in MCF10A cells, and oncogenesis in murine models. The PH-KD autoinhibitory interaction is weakened by E17K, providing a structural mechanistic basis. Multiple independent assays across multiple laboratories confirm a gain-of-function effect. Details ▾Hide ▴

Evidence considered

Constitutive AKT1 kinase activation demonstrated (PMID:17611497
PMID:23134728)
Altered PIP lipid specificity and pathological membrane association (PMID:18954143)
Growth factor-independent BaF3 survival and elevated pAKT (PMID:23134728)
Anchorage-independent growth and 3D acinar disruption (PMID:23134728)
In vivo oncogenesis with reduced survival in murine model (PMID:23134728)
Weakened PH-KD interdomain interaction by two-hybrid assay (PMID:23134728)

Sources

PMID:17611497 ↗PMID:21793738 ↗PMID:23134728 ↗17611497189541432179373823134728

PM1 ModerateThe variant resides at codon 17 within the pleckstrin homology (PH) domain of AKT1 (residues ~5-108), a critical functional domain essential for membrane localization, autoinhibition, and kinase regulation. The PH domain is a well-established mutational hotspot where pathogenic gain-of-function missense variants cluster and benign missense variation is notably absent. This variant lies in a statistically significant hotspot per the hotspots analysis. Multiple structural and functional studies (PMID:17611497, PMID:23134728) confirm that missense variants in the PH domain are overwhelmingly pathogenic. Details ▾Hide ▴

Evidence considered

Codon 17 in PH domain (critical functional domain)
PH domain is a well-established mutational hotspot lacking benign missense variation
Statistically significant hotspot confirmed
Structural studies show PH-KD interface disruption leads to constitutive activation

Sources

PMID:17611497 ↗PMID:23134728 ↗1761149723134728

PM2 SupportingThe variant is present in gnomAD v2.1 at an extremely low allele frequency (AF = 3.9999 × 10⁻⁶; 1/250,006 alleles; 0.0004%) and is absent from gnomAD v4.1. This frequency is well below the PM2 threshold of <0.1%, meeting the criterion for absent or extremely rare in population databases. The single observation in gnomAD v2.1 is in the European (non-Finnish) subpopulation (AF = 8.87 × 10⁻⁶). Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF = 0.0004% (1/250
006 alleles
<0.1% threshold)
gnomAD v4.1: absent
No homozygotes observed in any population database

Sources

gnomad_v2 ↗gnomad_v4 ↗

PP5 SupportingClinVar reports this variant as Pathogenic by 4 clinical laboratories (including Labcorp Genetics/Invitae and Variantyx), with review status 'criteria provided, single submitter'. Under generic ACMG/AMP, PP5 can be applied when a reputable clinical laboratory classifies the variant as pathogenic. Although the review status indicates only one submitter provided classification criteria, the concordance across 4 clinical laboratories supports application of PP5 at supporting strength. Details ▾Hide ▴

Evidence considered

ClinVar VariationID 13983: Pathogenic by 4 clinical laboratories (Invitae
Variantyx
OMIM submissions)

Still missing

ClinVar review status is 'criteria provided
single submitter'
expert panel consensus not available

Sources

clinvar ↗

Not met · 8 · evaluated, threshold not reached

PS4 PS4 requires statistically significant enrichment of the variant in affected individuals versus controls in a case-control study for a specific inherited disorder. The variant is observed in COSMIC (n=894) across multiple tumor types and in Proteus syndrome cases, but this is somatic/mosaic data from cancer cohorts, not a germline case-control study. Under generic ACMG/AMP, somatic enrichment in tumors does not independently satisfy germline PS4 without a formal case-control comparison. Details ▾Hide ▴

Evidence considered

COSMIC: 894 tumor samples
Proteus syndrome cases
no formal case-control study for inherited disorder

Still missing

No formal case-control study for a specific germline disorder with statistical comparison

Sources

PMID:21793738 ↗21793738

PP3 PP3 requires multiple lines of computational evidence supporting a deleterious effect. REVEL score is 0.51 (borderline; threshold for deleterious is typically >0.5). BayesDel score is 0.115701 (low). HCI prior is not available for AKT1. SpliceAI delta score is 0.01, predicting no splicing impact. The in silico evidence is equivocal and does not meet the threshold for multiple concordant lines of computational evidence supporting a deleterious effect. Details ▾Hide ▴

Evidence considered

REVEL: 0.51 (borderline)
BayesDel: 0.115701 (low)
SpliceAI: max delta 0.01 (no predicted splice impact)
HCI prior: not available

Still missing

In silico scores are equivocal
REVEL at borderline threshold

Sources

revelbayesdelspliceai ↗

BA1 BA1 requires allele frequency >1% in any general population database. gnomAD v2.1 AF = 0.0004% (far below 1%). gnomAD v4.1 reports the variant as absent. BA1 is not met. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF = 0.0004% (<< 1%)
gnomAD v4.1 absent

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 BS1 requires allele frequency >0.3% in population databases. gnomAD v2.1 AF = 0.0004% (0.0004% < 0.3%). gnomAD v4.1 reports the variant as absent. BS1 is not met. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF = 0.0004% (<< 0.3%)
gnomAD v4.1 absent

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS3 BS3 requires well-established functional studies showing NO damaging effect. Extensive functional evidence demonstrates the opposite: the E17K substitution results in constitutive AKT1 activation, altered lipid specificity, enhanced downstream signaling, transformation in cell-based assays, and oncogenesis in vivo (PMID:17611497, PMID:18954143, PMID:23134728). The functional data overwhelmingly supports a gain-of-function deleterious effect; BS3 is contradicted. Details ▾Hide ▴

Evidence considered

Functional studies consistently show gain-of-function/deleterious effect
contradicting BS3

Sources

PMID:17611497 ↗PMID:23134728 ↗176114971895414323134728

BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. REVEL score is 0.51 (borderline deleterious), BayesDel is 0.115701, and SpliceAI predicts no splicing impact. While the computational predictors are not strongly deleterious, they do not provide multiple concordant lines suggesting a benign effect. BP4 is not met; the in silico evidence is equivocal. Details ▾Hide ▴

Evidence considered

REVEL 0.51 (equivocal)
BayesDel 0.115701 (low)
SpliceAI no impact
no multiple concordant lines suggesting benign effect

Sources

revelbayesdelspliceai ↗

BP5 BP5 requires the variant to be found in a case with an alternate molecular basis for disease. The variant has been consistently found as the sole molecular finding in Proteus syndrome cases (PMID:21793738) and as a driver mutation in multiple cancer types. No cases with an alternate molecular etiology harboring this variant have been identified. Details ▾Hide ▴

Evidence considered

Variant is the primary molecular finding in Proteus syndrome
no cases with alternate molecular basis identified

Sources

PMID:21793738 ↗21793738

BP7 BP7 requires a synonymous variant for which splicing prediction algorithms predict no impact. This is a missense variant (c.49G>A, p.Glu17Lys), not a synonymous variant. BP7 is not applicable. Details ▾Hide ▴

Evidence considered

Missense variant
BP7 applies only to synonymous variants

Not assessed · 9 · no assessment recorded

PS1 PS1 requires a different nucleotide change at the same codon predicted to result in the same amino acid substitution that has been established as pathogenic. No independently curated pathogenic same-amino-acid change at codon 17 via a different nucleotide substitution was identified in ClinVar or the literature. Details ▾Hide ▴

Evidence considered

No alternate nucleotide change at codon 17 producing E17K with prior pathogenic classification found

Still missing

No curated pathogenic same-amino-acid comparator at codon 17 identified

PS2 PS2 requires a confirmed de novo occurrence with both parents tested and maternity/paternity confirmed. AKT1 c.49G>A (E17K) has been reported as a somatic mosaic mutation in Proteus syndrome (PMID:21793738), but no confirmed germline de novo event with parentage testing has been identified. The variant is primarily post-zygotic, not a germline de novo. Details ▾Hide ▴

Evidence considered

Somatic mosaic occurrence in Proteus syndrome reported
no germline de novo with confirmed parentage

Still missing

No confirmed germline de novo with both parents tested

Sources

PMID:21793738 ↗21793738

PM6 PM6 requires a confirmed de novo event with maternity and paternity testing. The variant has been reported as a somatic mosaic mutation in Proteus syndrome (PMID:21793738), identified in affected tissue but absent from unaffected tissue and parents. However, the variant is post-zygotic, not a confirmed germline de novo. PM6 is designed for germline de novo events with parentage confirmation, and the current evidence does not satisfy this requirement. Details ▾Hide ▴

Evidence considered

Somatic mosaic de novo in Proteus syndrome
no germline de novo with maternity/paternity confirmation

Still missing

No germline de novo with confirmed maternity and paternity

Sources

PMID:21793738 ↗21793738

PP1 PP1 requires co-segregation of the variant with disease in multiple affected family members. AKT1 c.49G>A (E17K) is a somatic mosaic variant primarily found in Proteus syndrome and cancers; it is not typically transmitted through the germline. No reports of multi-generational co-segregation in an affected family were identified in the literature. Details ▾Hide ▴

Evidence considered

Variant is somatic/mosaic
not transmitted in families
no co-segregation data available

Still missing

No family co-segregation data available for this primarily somatic variant

PP2 PP2 requires a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. While AKT1 missense variants (particularly in the PH domain) are associated with disease through gain-of-function, no VCEP-established gene-level constraint data confirming low benign missense rate was available for assessment under generic ACMG/AMP. Details ▾Hide ▴

Evidence considered

AKT1 missense variants are recognized as a disease mechanism
but no VCEP-validated gene constraint data to formally apply PP2

Still missing

No VCEP-validated gene-level constraint metrics for AKT1

PP4 PP4 requires the variant to be found in a patient whose phenotype or family history is highly specific for the disease with a single genetic etiology. While AKT1 E17K is strongly associated with Proteus syndrome (a distinctive overgrowth disorder) and has been observed in multiple cancer types, detailed individual patient phenotype data sufficient for PP4 adjudication was not available in the case materials. Details ▾Hide ▴

Evidence considered

Variant associated with Proteus syndrome (distinctive phenotype)
detailed individual patient data not available for formal PP4

Still missing

Individual patient phenotype data needed for formal PP4 assessment

Sources

PMID:21793738 ↗21793738

BS2 BS2 requires the variant to be observed in a healthy adult individual for a recessive or X-linked condition with full penetrance expected at an early age. AKT1-related conditions are autosomal dominant with variable expressivity, and the variant is primarily somatic/mosaic. No data on healthy adult carriers for formal BS2 assessment was available. Details ▾Hide ▴

Evidence considered

AKT1 conditions are dominant
no healthy adult carrier data available

Still missing

No data on asymptomatic adult carriers

BP2 BP2 requires observation of the variant in trans with a known pathogenic variant in a gene for a fully penetrant dominant disorder. AKT1 is a dominant gene, and observation of AKT1 E17K in trans with a known pathogenic AKT1 variant would argue against pathogenicity. However, no such observation has been reported and the variant is primarily somatic. Details ▾Hide ▴

Evidence considered

No data on co-occurrence in trans with a pathogenic AKT1 variant

Still missing

No trans co-occurrence data available

BP6 BP6 requires a reputable source to classify the variant as benign. No reputable source classifies AKT1 E17K as benign; ClinVar consistently reports Pathogenic (4 clinical laboratories). BP6 is not applicable. Details ▾Hide ▴

Evidence considered

ClinVar classifies as Pathogenic
no benign classification from any reputable source

Sources

clinvar ↗

Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AThis is a missense variant (c.49G>A, p.Glu17Lys) in AKT1; PVS1 applies only to predicted null variants (nonsense, frameshift, canonical ±1,2 splice sites, initiation codon, or exon deletions). The variant does not fall into any null-variant bucket per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴

Evidence considered

Missense variant (E17K)
not a null variant
outside canonical splice consensus

Sources

pvs1_generic_framework ↗

PM3 N/AAKT1-associated conditions follow autosomal dominant inheritance; PM3 applies only to recessive disorders requiring biallelic evidence. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to non-repeat in-frame deletions/insertions or stop-loss variants altering protein length; this is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 requires a different pathogenic missense variant at the same amino acid residue. Automated harvesting identified no confirmed same-residue comparator variants eligible for PM5 assessment at codon 17 of AKT1. Details ▾Hide ▴

Evidence considered

No pathogenic same-residue comparator variants confirmed at codon 17

Sources

pm5_candidates

BS4 N/ABS4 requires non-segregation with disease in affected family members. AKT1 E17K is a somatic mosaic variant not transmitted through families, making segregation analysis inapplicable. Details ▾Hide ▴

Evidence considered

Variant is somatic/mosaic
family segregation not evaluable

BP1 N/ABP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. AKT1 disease is driven by gain-of-function missense mutations, not loss-of-function truncating variants. The primary pathogenic mechanism for AKT1 is activating missense variants. Details ▾Hide ▴

Evidence considered

AKT1 disease mechanism is gain-of-function via missense variants
not loss-of-function via truncations

BP3 N/ABP3 applies only to in-frame deletions/insertions in a repetitive region; this is a single-nucleotide substitution. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 requires a different pathogenic variant at the same codon inherited from an affected parent. No such transmissible germline variant at codon 17 of AKT1 has been reported; the E17K variant is typically somatic/mosaic and not inherited. Details ▾Hide ▴

Evidence considered

No alternative pathogenic variant at codon 17 with germline inheritance identified

Identifiers

Gene: AKT1
Transcript: NM_001014431.1
Coding (HGVS c.): NM_001014431.1:c.49G>A
Protein (HGVS p.): NP_001014431.1:p.(Glu17Lys)
GRCh38: chr14:104780214 C>T
GRCh37: chr14:105246551 C>T
ClinVar: 13983
COSMIC: COSV62571334

Gene diagram

Every interpreted variant in AKT1, mapped onto the exon structure of NM_001014431.1. Select a row to find it on the plot.

AKT1NM_001014431.1

Fetching transcript structure from UCSC…

Exons

—

Transcript span

—

Strand

—

Variants mapped

—

Source

UCSC ncbiRefSeqCurated

All variants in AKT1 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 Allele count data not recorded

gnomAD v2.1 1 / 250,006 alleles AF 4e-06 · 0 homozygotes

gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD v2.1

AF 4e-06 · 1 / 250,006 alleles · 0 hom

European (non-Finnish)1 / 112,716

8.9e-06

0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +74 bp

0.010

SpliceAI acceptor gainat -3 bp

0.010

SpliceAI donor lossat +282 bp

0.000

SpliceAI donor gainat -126 bp

0.000

Pangolin splice lossmagnitude shown

-0.010

Pangolin splice gain

0.050

Other predictors

REVEL: 0.510
BayesDel: 0.116

How the predictions were used

Evidence considered

REVEL: 0.51 (borderline)
BayesDel: 0.115701 (low)
SpliceAI: max delta 0.01 (no predicted splice impact)
HCI prior: not available

Still missing

In silico scores are equivocal
REVEL at borderline threshold

Sources

revelbayesdelspliceai ↗

Evidence considered

REVEL 0.51 (equivocal)
BayesDel 0.115701 (low)
SpliceAI no impact
no multiple concordant lines suggesting benign effect

Sources

revelbayesdelspliceai ↗

Evidence considered

Missense variant
BP7 applies only to synonymous variants

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.51. BayesDel score = 0.115701.

9 paper records listed. 3 cited in the classification.

Cited in the classification

A transforming mutation in the pleckstrin homology domain of AKT1 in cancer.

Carpten JD et al. · 2007 Jul 26

Identified AKT1 E17K as a somatic gain-of-function mutation in breast, colorectal, and ovarian cancers. E17K constitutively activates AKT1 kinase, transforms NIH-3T3 cells, and induces leukemia in a murine model.
→ PS3 → PM1 Names this variant
PMID 17611497 ↗
A mosaic activating mutation in AKT1 associated with the Proteus syndrome.

Lindhurst MJ et al. · 2011 Aug 18

Identified AKT1 c.49G>A (E17K) as a somatic mosaic activating mutation in 26 of 29 patients with Proteus syndrome. The mutation was present in affected tissues but absent from unaffected tissues and parents, with mutant allele levels ranging from <1% to ~50%.
→ PS3 Names this variant
PMID 21793738 ↗
Source detail

Location Full-text file is ICMJE disclosure forms only; no paper text available
Disruption of PH-kinase domain interactions leads to oncogenic activation of AKT in human cancers.

Demonstrated that the E17K substitution weakens the PH-KD autoinhibitory interaction, leading to constitutive AKT1 phosphorylation (pT308, pS473). E17K promoted growth factor-independent BaF3 survival (>50× enrichment over WT), anchorage-independent growth (~20-fold colonies), disrupted 3D acinar morphogenesis in MCF10A cells, and reduced median survival to 19–20.5 days in a murine leukemia model. The E17K mutant showed reduced sensitivity to allosteric AKT inhibitors while retaining sensitivity to ATP-competitive inhibitors.
→ PS3 → PM1 Names this variant
PMID 23134728 ↗
Source detail

This mutation results in the substitution of glutamic acid at codon 17 of AKT1 with lysine (E17K) and alters the lipid-binding specificity of AKT, leading to pathological membrane association and constitutive signaling.

Location Abstract; Results paragraphs 1, 5–7; Figures 1A–G, 2C–D, 3A–F, 4; Discussion

Context BaF3 cell viability assay (IL-3 withdrawal); NIH 3T3 signaling and anchorage-independent growth; MCF10A 3D morphogenesis; mammalian two-hybrid (VP16/Gal4 luciferase); murine leukemia model (BaF3 xenograft); recombinant full-length AKT1 biochemical kinase assays with allosteric (Inhibitor VIII, GNE-929) and ATP-competitive (GNE-692, GSK690693) inhibitors

Other recorded publications

Activating E17K mutation in the gene encoding the protein kinase AKT1 in a subset of squamous cell carcinoma of the lung.

No paper-specific finding is recorded.

PMID 18256540 ↗
Oncogenic E17K mutation in the pleckstrin homology domain of AKT1 promotes v-Abl-mediated pre-B-cell transformation and survival of Pim-deficient cells.

No paper-specific finding is recorded.

PMID 20440266 ↗
Cancer associated E17K mutation causes rapid conformational drift in AKT1 pleckstrin homology (PH) domain.

No paper-specific finding is recorded.

PMID 23741320 ↗
National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers.

Sturgeon CM et al. · 2008

No paper-specific finding is recorded.

PMID 19042984 ↗
Screening for ovarian cancer: U.S. Preventive Services Task Force reaffirmation recommendation statement.

Moyer VA et al. · 2012

No paper-specific finding is recorded.

PMID 22964825 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

No paper-specific finding is recorded.

PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗

ClinVar 4 Pathogenic Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

ClinVar

This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories). (ClinVarID = 13983)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.51. BayesDel score = 0.115701.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV62571334, n = 894 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.