NM_001014431.1:c.49G>A

AKT1 · NP_001014431.1:p.(Glu17Lys) · NM_001014431.1

GRCh37: chr14:105246551 C>T · GRCh38: chr14:104780214 C>T

Gene: AKT1 Transcript: NM_001014431.1

Final call

Likely Pathogenic

PS3 strong PM1 moderate PM2 supporting PP5 supporting

Variant details

Gene

AKT1

Transcript

NM_001014431.1

Protein

NP_001014431.1:p.(Glu17Lys)

gnomAD AF

3.9999040023039446e-06 (v2.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This 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).	pvs1_generic_framework
PS1	Not assessed	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.
PS2	Not assessed	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.	PMID:21793738
PS3	Met	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.	PMID:17611497 PMID:21793738 PMID:23134728
PS4	Not met	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.	PMID:21793738
PS5	N/A	PS5 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.
PM1	Met	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.	PMID:17611497 PMID:23134728
PM2	Met	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).	gnomad_v2 gnomad_v4
PM5	N/A	PM5 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.	pm5_candidates
PM6	Not assessed	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.	PMID:21793738
PP1	Not assessed	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.
PP2	Not assessed	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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not assessed	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.	PMID:21793738
PP5	Met	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.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not assessed	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.
BS3	Not met	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.	PMID:17611497 PMID:23134728
BS4	N/A	BS4 requires non-segregation with disease in affected family members. AKT1 E17K is a somatic mosaic variant not transmitted through families, making segregation analysis inapplicable.
BP1	N/A	BP1 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.
BP2	Not assessed	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.
BP4	Not met	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.	revel bayesdel spliceai
BP5	Not met	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.	PMID:21793738
BP6	Not assessed	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.	clinvar
BP7	Not met	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.
BP3	N/A	BP3 applies only to in-frame deletions/insertions in a repetitive region; this is a single-nucleotide substitution.
PM3	N/A	AKT1-associated conditions follow autosomal dominant inheritance; PM3 applies only to recessive disorders requiring biallelic evidence.
PM4	N/A	PM4 applies to non-repeat in-frame deletions/insertions or stop-loss variants altering protein length; this is a missense substitution.

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