The AKT1 NM_001382430.1:c.49G>A (NP_001369359.1:p.(Glu17Lys)) missense variant has previously been reported in somatic cancers (COSMIC; COSV62571334, n = 894 times), and lies in a statistically significant hotspot (cancerhotspots.org). Experimental evidence: Independent biochemical, cellular, tissue, and in vivo assays consistently show activating effects, including approximately fourfold higher kinase activity and leukemia in 6/10 mice. Based on available guidelines, this variant is considered to be Pathogenic.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.AKT1 encodes a serine/threonine protein kinase that helps regulate cell growth, survival, metabolism, and other responses to growth signals through the PI3K/AKT pathway. Abnormal AKT1 activity is associated with excessive tissue growth syndromes, including Proteus syndrome and Cowden syndrome 6. AKT1 is an oncogene, and dysregulated signaling, activating mutations, and less commonly gene amplification contribute to several cancers, including breast, colorectal, and ovarian cancers.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
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.
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.
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.
Met at supporting: gnomAD v2.1 AF is 3.9999e-06, below the <=0.0001 PM2 threshold, and gnomAD v4.1 reports absence.
No benign criterion marked as applied in the recorded assessment.
Pathogenic: PS3 strong plus PS4 strong satisfy the generic ACMG/AMP rule for two strong pathogenic criteria, with PM1 moderate and PM2 supporting additional evidence.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1 allele counts were not recorded for this variant.
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).
Absent from gnomAD-Canada v1.0.
Recorded REVEL score: 0.510. Refer to the recorded PP3/BP4 rationale for interpretation.
4 Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
This variant has previously been reported in somatic cancers (COSMIC; COSV62571334, n = 894 times).
This variant lies in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 7 not met · 12 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
None of PS2, PM6, PP1, or BS4 can be assessed because the available evidence lacks case-specific parental testing, family history, affected-relative genotypes, and segregation data.
PS4 is met from the published affected-versus-unaffected sample counts after explicit OR and 95% CI calculation; PP4 is not assessed because the individual case phenotype is unavailable; PP5 and BP6 are not met because no exact-variant ClinVar expert-panel classification exists; BP5 is not assessed because no alternate molecular basis is documented.
Population evidence supports PM2 at supporting strength because the variant is absent from gnomAD v4.1 and extremely rare in gnomAD v2.1 (AF=3.9999040023039446e-06).
BA1 and BS1 are not met because the observed frequencies are far below their generic thresholds; BS2 is not assessed because no qualifying healthy adult carrier observation and full-penetrance early-onset inheritance context are documented.
No criteria match.
The exact AKT1 NM_001382430.1:c.49G>A (p.Glu17Lys) variant has been evaluated in multiple orthogonal functional systems with relevant controls. In NIH 3T3 cells, E17K produced approximately fourfold higher kinase activity than wild type, increased downstream phosphorylation, constitutive plasma-membrane localization, and cellular transformation; an in vivo mouse assay induced leukemia in 6/10 animals. Independent biochemical and live-cell studies showed a 7.7-fold increase in PI(3,4,5)P3 affinity, conversion to PI(4,5)P2 binding from an unmeasurable baseline to 130 ± 30 nM, an 18-fold slower dissociation rate, and constitutive plasma-membrane targeting. Patient-derived Proteus-syndrome tissues and mutant cell lines showed increased AKT phosphorylation, and a separate murine transformation model showed increased transformation, AKT signaling, survival, and resistance to imatinib-induced apoptosis, while also documenting that the mutation alone did not transform primary bone-marrow cells. The concordant biochemical, cellular, tissue, and in vivo results directly demonstrate an altered and activating AKT1 product effect for this exact variant, satisfying the generic PS3 definition. The evidence is strong rather than moderate because the variant-specific effect is reproducible across several independent assay types and includes physiologically relevant tissue and in vivo observations; no BS3-supportive result was identified.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
The exact AKT1 c.49G>A (p.Glu17Lys) variant was reported in 75 of 97 clinically affected Proteus-syndrome tissue samples and 13 of 41 unaffected tissue samples in PMID:21793738. Treating these reported affected and unaffected sample counts as a case-control comparison, I computed the odds ratio as (75/22)/(13/28) = 7.34 with an approximate Woolf 95% CI of 3.26-16.53. The OR is >5.0 and the confidence interval excludes 1.0, satisfying the generic PS4 note. Human review is warranted because the comparison is based on mosaic tissue samples, including multiple samples from patients, rather than independent individuals. PMID:17611497 reported the variant in 5/61 breast, 3/51 colorectal, and 1/50 ovarian cancers, but did not provide an unaffected control cohort and therefore was not used for the threshold calculation.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
p.Glu17Lys lies at residue 17 in the AKT1 pleckstrin homology domain. PMID:17611497 reports the recurrent E17K mutation in the pleckstrin homology domain and identifies its position in the lipid-binding pocket; the study also reports recurrent occurrence in breast, colorectal, and ovarian cancers. PMID:18954143 demonstrates that E17K alters the PH-domain phosphoinositide-binding specificity and membrane targeting. The case evidence also records that the variant lies in a statistically significant hotspot. No benign-variation signal for the relevant functional site is documented in the supplied evidence, and vcep_materials.json has no AKT1 domain-table entry requiring additional domain-boundary review.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
PM2 is met at supporting strength. Under the supplied generic SVI threshold of <=0.0001, the variant has an all-comers gnomAD v2.1 exome AF of 3.9999040023039446e-06 (1/250006 alleles; zero homozygotes), with the highest population AF 8.871854927428227e-06, and is absent from gnomAD v4.1. No governing VCEP requires a non-cancer or exome-only subset here, so the all-comers totals are the applicable default; the non-cancer datasets are also reported absent.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
PP3 is applicable because NM_001382430.1:c.49G>A is a missense variant, NM_001382430.1:c.49G>A (p.Glu17Lys), so the governing generic path is REVEL only. The REVEL score is 0.51, below the generic PP3 supporting threshold of >= 0.644 calibrated by Pejaver et al. 2022 (PMID:36413997), and therefore does not support PP3 at any strength. SpliceAI max delta 0.009 is not used because splice prediction is not the governing path for a missense variant; BayesDel is not used because no generic ACMG-strength calibration is established.
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997) ... Missense variant -> REVEL only.
ClinVar contains exact-variant Pathogenic submissions, but the ClinVar audit reports zero expert-panel submissions. The available records are ordinary laboratory or literature-only submissions, not an exact-variant ClinVar expert-panel classification. Therefore the generic PP5 trigger is not met.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. Under the generic ACMG/AMP stand-alone threshold of >=0.05, the highest reported all-comers gnomAD v2.1 allele frequency is 8.871854927428227e-06 in the European non-Finnish population (1/112716 alleles), and the overall frequency is 3.9999040023039446e-06 (1/250006 alleles); gnomAD v4.1 reports the variant as absent. These values are far below 5%.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BS1 is not met. The generic default threshold is >=0.01, while the highest all-comers gnomAD v2.1 frequency is 8.871854927428227e-06 and the overall frequency is 3.9999040023039446e-06; gnomAD v4.1 reports absence. The observed frequency is therefore approximately 1,127-fold below 1% even before a disorder-specific maximum-credible-frequency calculation. The case does not provide a governing VCEP threshold or a prevalence, penetrance, and allelic-heterogeneity model that would justify a different BS1 threshold.
Allele frequency is greater than expected for the disorder.
BS3 is not met. The exact AKT1 p.Glu17Lys variant is directly tested in multiple biochemical, cellular, tissue, and in vivo studies, but the results consistently show altered or activating function rather than no damaging effect: increased lipid binding and membrane targeting, increased kinase activity and AKT-pathway phosphorylation, cellular transformation or survival effects, and an in vivo leukemia phenotype. No well-established assay result demonstrating preserved protein function or normal splicing was identified. Because the available functional evidence is directionally opposite to the BS3 requirement, this criterion is not met rather than not assessed.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
BP4 is applicable because NM_001382430.1:c.49G>A is a missense variant, NM_001382430.1:c.49G>A (p.Glu17Lys), so the governing generic path is REVEL only. The REVEL score is 0.51, above the generic BP4 supporting threshold of <= 0.29 calibrated by Pejaver et al. 2022 (PMID:36413997), so BP4 is not met. The SpliceAI max delta 0.009 is not substituted for the gray-zone REVEL result because splice prediction is not the governing path for a missense variant; BayesDel is not used because no generic ACMG-strength calibration is established.
BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997) ... Missense variant -> REVEL only.
The exact-variant ClinVar record contains Pathogenic, Oncogenic, or non-classification submissions and no exact-variant expert-panel Benign or Likely benign classification. Ordinary laboratory submissions and aggregate labels cannot trigger BP6 under the specified generic rule.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The variant is p.Glu17Lys, but the supplied evidence documents the same c.49G>A nucleotide change rather than a previously established pathogenic variant producing the same amino-acid change through a different nucleotide change. No qualifying alternate-codon PS1 comparator was identified.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
The available evidence does not establish a germline de novo occurrence in a patient with the disease. PMID:21793738 reports AKT1 c.49G>A as a somatic mosaic mutation in Proteus syndrome tissues, with peripheral blood usually negative, but provides no maternity confirmation, paternity confirmation, or family-history assessment for this case. Therefore, the PS2 requirements cannot be assessed; the somatic mosaic observations must not be treated as confirmed germline de novo evidence.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The variant is p.Glu17Lys, but no different missense substitution at residue 17 with an established pathogenic determination is documented in the supplied evidence. The PM5 candidate file contains zero same-residue candidates.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
The available evidence does not establish an assumed de novo variant in this patient. PMID:21793738 describes somatic mosaic AKT1 c.49G>A in Proteus syndrome tissues, not a proband-specific de novo event, and no parental testing or family-history information is available. Thus PM6 cannot be assessed from the available evidence.
Assumed de novo, but without confirmation of paternity and maternity.
No affected family members, familial genotypes, or meioses are documented. The available literature concerns somatic mosaic Proteus syndrome cases and does not provide segregation of this variant with disease across multiple affected relatives. PP1 therefore cannot be assessed.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
The supplied evidence establishes that AKT1 p.Glu17Lys is a recurrent activating variant, but it does not establish the gene-level prerequisites for PP2: a low rate of benign missense variation and missense variants as a common disease mechanism. The available gnomAD observation for this variant is not a gene-wide benign-missense rate or mechanism assessment.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The available evidence describes Proteus syndrome in the published cohort, but does not provide the clinical phenotype or family history for the individual case being adjudicated. Therefore, the specificity of this patient's phenotype for a disease with a single genetic etiology cannot be assessed.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS2 is not assessed. The available population data show one heterozygous allele in gnomAD v2.1 and no homozygotes, but do not identify that carrier as a healthy adult with documented age, phenotype, or full penetrance expectations. The case also does not establish a germline dominant, recessive, or X-linked disorder and its exact-variant literature describes somatic or mosaic observations, which cannot by themselves satisfy the healthy-adult BS2 requirement.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
No affected family members with known variant status are documented, so there is no informative non-segregation observation. The available literature does not report a family in which this variant is absent from affected relatives. BS4 therefore cannot be assessed.
Lack of segregation in affected members of a family.
The supplied evidence does not establish that AKT1 is a gene for which primarily truncating variants are known to cause disease. The documented p.Glu17Lys evidence concerns an activating missense mechanism and cannot by itself establish the gene-level truncating-variant pattern required for BP1.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
BP2 requires observation of the assessed variant in trans with a pathogenic variant for a fully penetrant dominant gene/disorder, or in cis with a pathogenic variant in any inheritance pattern. The available reports document somatic or mosaic occurrence of AKT1 c.49G>A (p.Glu17Lys), but provide no affected-proband observation with a second pathogenic variant and no parental, offspring, tumor-clone, or other phase result establishing cis or trans. The criterion therefore cannot be assessed from the available evidence.
BP2: Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
No evidence in the reviewed case materials establishes that the exact variant was found in a case with an alternate molecular basis for disease. Cancer studies and the Proteus-syndrome study report the variant in disease-associated samples, but do not demonstrate an alternate molecular cause for the relevant case.
Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_001382430.1:c.49G>A in AKT1 is a missense substitution predicted to produce NP_001369359.1:p.(Glu17Lys). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for AKT1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM3 is limited to recessive disorders and requires the assessed variant to be detected in trans with a pathogenic variant. The available case evidence describes AKT1 c.49G>A (p.Glu17Lys) as a somatic mosaic activating variant associated with Proteus syndrome and as a somatic cancer variant, with no evidence that this case concerns a recessive AKT1 disorder. Therefore the recessive PM3 applicability condition is not met, and PM3 is not applicable.
PM3: For recessive disorders, detected in trans with a pathogenic variant
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_001382430.1:c.49G>A in AKT1 is a missense substitution predicted to produce NP_001369359.1:p.(Glu17Lys). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for AKT1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_001382430.1:c.49G>A in AKT1 is a missense substitution predicted to produce NP_001369359.1:p.(Glu17Lys). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for AKT1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001382430.1:c.49G>A in AKT1 is a missense substitution predicted to produce NP_001369359.1:p.(Glu17Lys). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for AKT1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in AKT1, mapped onto the exon structure of NM_001382430.1. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (non-Finnish)1 / 112,716 | 8.9e-06 |
Absent from gnomAD v4.1.
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).
Absent from gnomAD-Canada v1.0.
PP3 is applicable because NM_001382430.1:c.49G>A is a missense variant, NM_001382430.1:c.49G>A (p.Glu17Lys), so the governing generic path is REVEL only. The REVEL score is 0.51, below the generic PP3 supporting threshold of >= 0.644 calibrated by Pejaver et al. 2022 (PMID:36413997), and therefore does not support PP3 at any strength. SpliceAI max delta 0.009 is not used because splice prediction is not the governing path for a missense variant; BayesDel is not used because no generic ACMG-strength calibration is established.
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997) ... Missense variant -> REVEL only.
BP4 is applicable because NM_001382430.1:c.49G>A is a missense variant, NM_001382430.1:c.49G>A (p.Glu17Lys), so the governing generic path is REVEL only. The REVEL score is 0.51, above the generic BP4 supporting threshold of <= 0.29 calibrated by Pejaver et al. 2022 (PMID:36413997), so BP4 is not met. The SpliceAI max delta 0.009 is not substituted for the gray-zone REVEL result because splice prediction is not the governing path for a missense variant; BayesDel is not used because no generic ACMG-strength calibration is established.
BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997) ... Missense variant -> REVEL only.
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001382430.1:c.49G>A in AKT1 is a missense substitution predicted to produce NP_001369359.1:p.(Glu17Lys). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for AKT1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.51. BayesDel score = 0.115701.
6 paper records listed. 5 cited in the classification.
A G . A point mutation at nucleotide 49 that results in a lysine substitution for glutamic acid at amino acid 17 (AKT(E17K)) was identified in 5 of 61 (8%) breast, 3 of 51 (6%) colorectal and 1 of 50 (2%) ovarian cancers (Supplementary Table 1 and Supplementary Fig. 1).
Location Results, ‘Identification of a mutation in the PHD of AKT1’
Context Tumor sequencing of 61 breast, 51 colorectal, and 50 ovarian cancers; structural analysis of the AKT1 pleckstrin homology domain; functional assays in NIH 3T3 and Rat1 cells; adoptive-transfer leukemia assay in Em-Myc mouse hematopoietic cells.
We found a heterozygous G→A transition at nucleotide 49 in two samples out of 118 analysed: P-LC34 and M-LC84.
Location Results and Discussion, Mutation analysis of AKT1 in human lung cancer cell lines and carcinomas; Table 1B
Context Direct sequencing of AKT1 exon 4 in primary lung carcinoma specimens, with paired tumor/adjacent-normal tissue analysis and endogenous kinase assays.
The E17K mutation substantially weakens the specificity of the AKT1 PH domain, converting it from a PI(3,4,5)P3-specific domain into a PI(3,4,5)P3- and PI(4,5)P2-binding domain.
Location Results, Quantification of PIP Lipid Affinities and Selectivities; Kinetic Analysis of PIP Lipid On- and Off-Rates; Effects on Membrane Targeting in Live Cells; Table 2
Context In vitro competitive displacement and stopped-flow fluorescence assays using isolated human AKT1 PH domains and synthetic plasma-membrane vesicles, plus live-cell fluorescence imaging in serum-starved NIH 3T3 fibroblasts.
DNA sequence analysis revealed that the aberrant bands represented an identical point mutation in the pleckstrin homology domain of mice AKT1 (G4A mutation at nucleotide 49 that results in a lysine substitution for glutamic acid at amino-acid 17 (AKT1(E17K)) (Supplementary Figure S1).
Location Results, “AKT1(E17K) mutation was identified in a small proportion of v-Abl transformants”
Context PCR-SSCP and sequencing of 116 v-Abl-transformed murine cell clones, followed by retroviral expression and assays of transformation, apoptosis, AKT activity/localization, BCL2/BAD signaling, and survival.
Using several filters and VarSifter Next-Gen filtering software to analyze the variants, we identified a variant in AKT1, c.49G→A (predicting a substitution of lysine for glutamine at amino acid 17), in Patient 5, with the use of the affected–unaffected comparison filter. On manual examination, we found that 7 exomes that we analyzed had this variant (2 exomes from 3 patients and 1 exome from a fourth patient). The proportion of mutant sequence reads in these samples ranged from 3.6 to 51% (Table 2 in the Supplementary Appendix). The AKT1 c.49G→A variant was absent in 401 ClinSeq research subjects9 in dbSNP, version 130, and was found in a single read in the 1000 Genomes project.10
Location Results, Variant Filtering; Sample Survey; Functional Characterization
Context Exome sequencing of affected and unaffected tissues, Sanger sequencing, restriction-enzyme digestion assay, and cell-line/clonal functional assays measuring AKT1 phosphorylation at Ser473 and Thr308 in patients with Proteus syndrome.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
Absent from gnomAD v4.1.
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).
Absent from gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories). (ClinVarID = 13983)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.51. BayesDel score = 0.115701.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV62571334, n = 894 times).
This variant lies in a statistically significant hotspot.