Variant classification summary

NM_001382430.1:c.49G>A

AKT1 · NP_001369359.1:p.(Glu17Lys) · NM_001382430.1

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

Gene: AKT1 Transcript: NM_001382430.1

Final call

Pathogenic

PS3 strong PS4 strong PM1 moderate PM2 supporting

Variant details

Gene

AKT1

Transcript

NM_001382430.1

Protein

NP_001369359.1:p.(Glu17Lys)

gnomAD AF

3.9999040023039446e-06 (v2.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PS3 strong assays consistently show activating effects for p.Glu17Lys.

2

Pathogenic: PS4 strong affected-versus-unaffected samples yielded OR 7.34 (95% CI 3.26–16.53).

3

Pathogenic: PM1 moderate places p.Glu17Lys in AKT1's critical PH-domain lipid-binding hotspot.

4

Pathogenic: PM2 supporting shows extreme rarity in gnomAD v2.1 and absence from gnomAD v4.1.

Final determination: Under the generic ACMG/AMP 2015 fallback, two strong pathogenic criteria (PS3 and PS4) satisfy the Pathogenic combination rule; PM1 and PM2 add supporting evidence.

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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no qualifying pathogenic alternate-nucleotide change producing the same p.Glu17Lys amino-acid substitution was documented.
PS2	Not assessed	Not assessed: no parental testing or family-history data confirm germline de novo status, and the relevant report describes somatic mosaicism instead.	PMID:21793738
PS3	Met	Met (strong): independent biochemical, cellular, tissue, and in vivo assays consistently show activating effects, including approximately fourfold higher kinase activity and leukemia in 6/10 mice.	PMID:17611497 PMID:18954143 PMID:20440266 PMID:21793738
PS4	Met	Met: affected versus unaffected samples yielded OR 7.34 (95% CI 3.26-16.53), exceeding the >5.0 threshold with a confidence interval excluding 1.0.	PMID:21793738 PMID:17611497
PM1	Met	Met: p.Glu17Lys is in AKT1's critical pleckstrin homology lipid-binding domain and lies in a statistically significant hotspot without documented benign variation at the site.	PMID:17611497 PMID:18954143
PM2	Met	Met at supporting: gnomAD v2.1 AF is 3.9999e-06, below the <=0.0001 PM2 threshold, and gnomAD v4.1 reports absence.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: available reports describe AKT1 p.Glu17Lys as somatic or mosaic, not as an allele in a recessive disorder detected in trans.	PMID:21793738 PMID:17611497
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different pathogenic missense substitution at AKT1 residue 17 was documented for comparison with p.Glu17Lys.	pm5_candidates
PM6	Not assessed	Not assessed: no proband-specific de novo observation is documented, and no parental testing or family-history information is available.	PMID:21793738
PP1	Not assessed	Not assessed: no affected relatives, familial genotypes, or segregation meioses are documented for this variant.
PP2	Not assessed	Not assessed: gene-wide benign-missense rate and evidence that missense is AKT1's common disease mechanism were not established.
PP3	Not met	Not met: REVEL 0.51 is below the PP3 supporting threshold of >=0.644 for missense variants.	revel
PP4	Not assessed	Not assessed: the individual case phenotype and family history are not provided, so phenotype specificity cannot be established.
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel classification, only laboratory or literature-only Pathogenic submissions.	clinvar
BA1	Not met	Not met: the highest gnomAD v2.1 allele frequency is 8.87e-06, far below the 5% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the highest gnomAD v2.1 frequency is 8.87e-06, approximately 1,127-fold below the generic 1% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD shows one heterozygous allele but does not document a healthy adult carrier or the required full-penetrance inheritance context.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: exact-variant assays consistently show altered or activating function, including approximately fourfold higher kinase activity, rather than no damaging effect.	PMID:17611497 PMID:18954143 PMID:20440266 PMID:21793738
BS4	Not assessed	Not assessed: no affected relatives with known variant status are available to demonstrate lack of segregation.
BP1	Not assessed	Not assessed: a gene-level pattern of primarily truncating AKT1 disease variants was not established by the supplied evidence.
BP2	Not assessed	Not assessed: no cis or trans phase result with a pathogenic variant is reported for AKT1 p.Glu17Lys.	PMID:21793738 PMID:17611497
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.51 is above the BP4 supporting threshold of <=0.29 for missense variants.	revel
BP5	Not assessed	Not assessed: no documented case shows the exact variant alongside an alternate molecular basis for the disease.	PMID:21793738 PMID:17611497
BP6	Not met	Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification is present.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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