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).1 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).2 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).3 ClinVar reports this variant as Pathogenic by 4 clinical laboratories including Labcorp Genetics/Invitae and Variantyx (PP5_Supporting).4 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.5 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).6
AKT1
Final classification
Likely Pathogenic
AKT1 c.49G>A · p.Glu17Lys
AKT1
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).
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.
Classification rationale
PS3PM1PM2PP5
Likely Pathogenic
AKT1 c.49G>A
PS3 + PM1 + PM2 + PP5
→
Likely Pathogenic
5
revelbayesdelspliceai ↗
6
generic_acmg_combination_rules
Gene diagram
· NM_001014431.1 · variants mapped to exon structure
AKT1
NM_001014431.1
Fetching transcript structure from UCSC…
Applied criteria · 4 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
Population frequency
“
Absent from gnomAD v4.1.
Overall AF
1 / 250,006
0.0004%
Highest · European (non-Finnish)
0.00089%
Homozygotes
0
Allele frequency by ancestry — gnomAD v2.1
observed in 1 of 8 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| European (non-Finnish) | 1 / 112,716 | 0.00089% | 0 |
| African/African American | 0 / 16,118 | — | — |
| Admixed American | 0 / 34,504 | — | — |
| Ashkenazi Jewish | 0 / 10,020 | — | — |
| East Asian | 0 / 18,380 | — | — |
| European (Finnish) | 0 / 21,592 | — | — |
| Remaining individuals | 0 / 6,104 | — | — |
| South Asian | 0 / 30,572 | — | — |
“
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).
“
This variant is absent from gnomAD-Canada.
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
Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV62571334, n = 894 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · 31 PMIDs triaged · 8 high-priority
31papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
17611497 ↗
functional
A transforming mutation in the pleckstrin homology domain of AKT1 in cancer.
Although AKT1 (v-akt murine thymoma viral oncogene homologue 1) kinase is a central member of possibly the most frequently activated proliferation and survival pathway in cancer, mutation of AKT1 has not been widely reported. Here we report the identification of a somatic mutation in human breast, colorectal and ovarian cancers that results in a glutamic acid to lysine substitution at amino acid 1
BS3PM1PS3
21793738 ↗
functional
A mosaic activating mutation in AKT1 associated with the Proteus syndrome.
The Proteus syndrome is characterized by the overgrowth of skin, connective tissue, brain, and other tissues. It has been hypothesized that the syndrome is caused by somatic mosaicism for a mutation that is lethal in the nonmosaic state. We performed exome sequencing of DNA from biopsy samples obtained from patients with the Proteus syndrome and compared the resultant DNA sequences with those of u
BS3PM1PS3
17611497 ↗
functional
A transforming mutation in the pleckstrin homology domain of AKT1 in cancer.
Although AKT1 (v-akt murine thymoma viral oncogene homologue 1) kinase is a central member of possibly the most frequently activated proliferation and survival pathway in cancer, mutation of AKT1 has not been widely reported. Here we report the identification of a somatic mutation in human breast, colorectal and ovarian cancers that results in a glutamic acid to lysine substitution at amino acid 1
BS3PP5PS3PS4
18256540 ↗
functional
Activating E17K mutation in the gene encoding the protein kinase AKT1 in a subset of squamous cell carcinoma of the lung.
Somatic mutation (E17K) that constitutively activates the protein kinase AKT1 has been found in human cancer patients. We determined the role of the E17K mutation of AKT1 in lung cancer, through sequencing of AKT1 exon 4 in 105 resected, clinically annotated non-small cell lung cancer specimens. We detected a missense mutations G-->A transition at nucleotide 49 (that results in the E17K substit
BS3PM1PS3
20440266 ↗
functional
Oncogenic E17K mutation in the pleckstrin homology domain of AKT1 promotes v-Abl-mediated pre-B-cell transformation and survival of Pim-deficient cells.
Abl-mediated transformation requires the activation of multiple pathways involved in the cellular proliferation and survival, including PI3K/AKT and JAK/STAT-dependent Pim kinases. Recently, the E17K mutation in the AKT1 has been associated with multiple human malignancies and leukemia in mice. However, this mutation has not been identified in Abl-transformed cells. We investigated the presence of
BS3PM1PS3
21793738 ↗
functional
A mosaic activating mutation in AKT1 associated with the Proteus syndrome.
The Proteus syndrome is characterized by the overgrowth of skin, connective tissue, brain, and other tissues. It has been hypothesized that the syndrome is caused by somatic mosaicism for a mutation that is lethal in the nonmosaic state. We performed exome sequencing of DNA from biopsy samples obtained from patients with the Proteus syndrome and compared the resultant DNA sequences with those of u
BS3PP5PS3PS4
23134728 ↗
functional
Disruption of PH-kinase domain interactions leads to oncogenic activation of AKT in human cancers.
The protein kinase v-akt murine thymoma viral oncogene homolog (AKT), a key regulator of cell survival and proliferation, is frequently hyperactivated in human cancers. Intramolecular pleckstrin homology (PH) domain-kinase domain (KD) interactions are important in maintaining AKT in an inactive state. AKT activation proceeds after a conformational change that dislodges the PH from the KD. To under
BS3PM1PS3
23741320 ↗
functional
Cancer associated E17K mutation causes rapid conformational drift in AKT1 pleckstrin homology (PH) domain.
AKT1 (v-akt murine thymoma viral oncogene homologue 1) kinase is one of the most frequently activated proliferated and survival pathway of cancer. Recently it has been shown that E17K mutation in the Pleckstrin Homology (PH) domain of AKT1 protein leads to cancer by amplifying the phosphorylation and membrane localization of protein. The mutant has shown resistance to AKT1/2 inhibitor VIII drug mo
BS3PM1PS3
19042984 ↗
background review
National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers.
PP5PS4
22964825 ↗
background review
Screening for ovarian cancer: U.S. Preventive Services Task Force reaffirmation recommendation statement.
PP5PS4
28492532 ↗
background review
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
PS3PS4
Sources & reference links