About AKT1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
AKT1 c.235_238delinsAAGG, p.(Gln79_Trp80delinsLysGly)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM1Moderate
PM1 · moderate
This variant alters residues Gln79 and Trp80, which lie within a statistically significant mutational hotspot in the AKT1 pleckstrin homology (PH) domain as determined by CancerHotspots.org. The PH domain is critical for membrane recruitment and kinase activation, and this region has no observed benign variation in population databases.
PM2Moderate
PM2 · moderate
This variant is absent from all population databases, including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), with zero alleles observed across all populations. Allele frequency is 0.00%, well below the PM2 threshold of 0.1% for a non-VCEP framework.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 moderate; combination = 2 moderate, which maps to VUS.
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
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.060 maximum delta
Recorded SpliceAI maximum delta score: 0.060. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. AKT1, an intracellular kinase, is altered predominantly by mutation in various cancer types including breast and endometrial cancers.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 2 not met · 18 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
PM1 is met at moderate strength: the variant alters residues Gln79 and Trp80 within a statistically significant CancerHotspots mutational hotspot in the AKT1 PH domain, a critical functional region with no observed benign variation.
PM2 is met at moderate strength: the variant is absent from all gnomAD populations (v2.1 exomes, v4.1 exomes, Canada genomes), with an allele frequency of 0.00%.
Two moderate pathogenic criteria (PM1 + PM2) are insufficient to reach a likely pathogenic classification under generic ACMG/AMP 2015 combination rules (PMID:25741868), which require either 1 very strong + 1 moderate, or 1 strong + 2 moderate, or 2 moderate criteria. The variant is classified as a variant of uncertain significance (VUS).
PVS1 is not applicable: Mutalyzer normalization resolves the variant to two adjacent missense substitutions (p.Q79K, p.W80G) rather than a null variant.
PS3 (functional studies), PS4 (case-control), PP1 (cosegregation), and multiple other criteria could not be assessed due to absence of variant-specific data in ClinVar, gnomAD, COSMIC, and the literature.
No criteria match.
Met · 2
PM1 ModerateThis variant alters residues Gln79 and Trp80, which lie within a statistically significant mutational hotspot in the AKT1 pleckstrin homology (PH) domain as determined by CancerHotspots.org. The PH domain is critical for membrane recruitment and kinase activation, and this region has no observed benign variation in population databases. Details ▾Hide ▴
Evidence considered
- CancerHotspots: residues Q79 and W80 lie within a statistically significant hotspot
- PH domain (residues ~1-110) is a critical functional domain for membrane recruitment
- Absent from gnomAD
- consistent with no benign variation in this region
Sources
PM2 ModerateThis variant is absent from all population databases, including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), with zero alleles observed across all populations. Allele frequency is 0.00%, well below the PM2 threshold of 0.1% for a non-VCEP framework. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (AF = 0.00%)
- gnomAD v4.1: absent (AF = 0.00%)
- gnomAD-Canada v1.0: absent (AF = 0.00%)
Sources
Not met · 2 · evaluated, threshold not reached
BA1 Allele frequency is 0.00% in gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the BA1 threshold of >1% in any population. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF = 0.00%
- gnomAD v4.1: AF = 0.00%
- gnomAD-Canada v1.0: AF = 0.00%
Sources
BS1 Allele frequency is 0.00% in gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the BS1 threshold of >0.3% in any population. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF = 0.00%
- gnomAD v4.1: AF = 0.00%
- gnomAD-Canada v1.0: AF = 0.00%
Sources
Not assessed · 18 · no assessment recorded
PS1 No known pathogenic missense variant at the same amino acid positions (Gln79, Trp80) or with the same amino acid changes (Q79K, W80G) was identified in ClinVar or the literature to support PS1. Details ▾Hide ▴
Evidence considered
- ClinVar: absent for this variant
- no comparator at same residues identified
Still missing
- No known pathogenic comparator at residues Q79 or W80
Sources
PS2 No de novo observation with confirmed maternity and paternity has been reported for this variant. Details ▾Hide ▴
Still missing
- No de novo data available
PS3 No variant-specific functional studies were identified. OncoKB reports no variant-specific reviewed functional evidence; gene-level curated context is available but insufficient to meet PS3. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Likely Oncogenic (gene-level
- not variant-specific)
- OncoKB: no variant-specific reviewed functional evidence
Still missing
- No variant-specific functional assays identified
Sources
PS4 No case-control or prevalence data comparing affected vs. unaffected individuals are available for this variant. Details ▾Hide ▴
Still missing
- No case-control or cohort prevalence data
PM6 No de novo observation (with or without confirmed maternity/paternity) has been reported for this variant. Details ▾Hide ▴
Still missing
- No de novo reports
PP1 No cosegregation data in affected families is available for this variant. Details ▾Hide ▴
Still missing
- No cosegregation data
PP2 HCI prior score for AKT1 is not available (gene not supported by the HCI prior database). Unable to assess whether AKT1 has a low rate of benign missense variation as required by PP2. Details ▾Hide ▴
Evidence considered
- HCI prior: not found for AKT1
Still missing
- No missense constraint metric available for AKT1
PP3 REVEL and BayesDel scores are unavailable because the pipeline classified this variant as a non-SNV during prefetch, though Mutalyzer normalization reveals it consists of two adjacent substitutions (c.235C>A, c.238T>G). SpliceAI max delta score is 0.06, indicating no significant splicing impact. Insufficient computational evidence to assess deleterious protein effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.06 (no significant splice impact)
- REVEL: skipped (pipeline classification as non-SNV)
- BayesDel: skipped (pipeline classification as non-SNV)
Still missing
- REVEL/BayesDel scores could not be computed
- individual SNV scores for c.235C>A and c.238T>G may be informative if obtained manually
Sources
PP4 No patient phenotype or clinical data are available to assess whether the phenotype is specific for AKT1-related disease. Details ▾Hide ▴
Still missing
- No patient phenotype data
PP5 This variant is absent from ClinVar. No reputable source (clinical diagnostic laboratory, expert panel) has reported this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar: variant absent
- no submissions from any source
Still missing
- No ClinVar classification available
Sources
BS2 No data on observation of this variant in healthy adult controls with full penetrance expected at an early age. Details ▾Hide ▴
Still missing
- No healthy control data
BS3 No well-established functional studies demonstrating no deleterious effect have been identified for this variant. Details ▾Hide ▴
Still missing
- No functional studies demonstrating benign effect
BS4 No segregation data in affected families is available to assess lack of cosegregation with disease. Details ▾Hide ▴
Still missing
- No segregation data
BP1 AKT1 has both gain-of-function (activating missense variants such as E17K) and loss-of-function germline disease mechanisms reported. It is unclear whether missense variants should be considered benign by default under BP1, which requires a gene where primarily truncating variants cause disease. Details ▾Hide ▴
Evidence considered
- AKT1 LoF mechanism supported for germline disease per PVS1 gene context
- AKT1 also has well-established activating missense alterations (e.g.
- E17K in Proteus syndrome)
Still missing
- Unclear whether AKT1 disease mechanism is primarily truncating
- mixed LoF/GoF landscape
Sources
pvs1_gene_context
BP4 No multiple lines of computational evidence are available to suggest no impact on gene product. SpliceAI delta score is 0.06 (no significant splice impact), but REVEL and BayesDel scores are unavailable. SpliceAI alone is insufficient for BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.06 (no splice impact)
- REVEL/BayesDel: unavailable (pipeline classified as non-SNV)
Still missing
- No protein-level in silico scores available
Sources
BP5 No data available on whether this variant has been observed in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
- No alternate molecular basis data
BP6 This variant is absent from ClinVar. No reputable source has reported it as benign. Details ▾Hide ▴
Evidence considered
- ClinVar: variant absent
Still missing
- No ClinVar benign classification
Sources
PS5 No data available on whether affected individuals carrying this variant also harbor an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
- No alternate molecular basis data
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot a null variant. Mutalyzer normalization resolves NM_001014431.1:c.235_238delCAGTinsAAGG to two adjacent missense substitutions (c.235C>A, p.Q79K and c.238T>G, p.W80G) rather than a frameshift, nonsense, or canonical splice site variant. The variant does not fall into any ClinGen SVI PVS1 null-variant bucket (PMC6185798). Details ▾Hide ▴
Evidence considered
- PVS1 gene gate: eligible (AKT1 LoF mechanism supported for germline disease)
- Variant assessment bucket: other (not nonsense
- frameshift
- or canonical ±1
- 2 splice)
- apply_generic_pvs1_framework: false
Sources
PM3 N/ASkipped per adjudication directive. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ANo net protein length change. The variant deletes 4 nucleotides and inserts 4 nucleotides, preserving the reading frame. Mutalyzer normalization resolves it to two adjacent missense substitutions (c.235C>A and c.238T>G) rather than an in-frame deletion/insertion, and PM4 requires a protein length alteration. Details ▾Hide ▴
Evidence considered
- Net nucleotide change: 4 bp deleted
- 4 bp inserted
- no length change
- Normalized form: two missense substitutions (Q79K
- W80G)
- No stop-loss or in-frame length alteration
Sources
pvs1_variant_assessment
PM5 N/AUnable to parse classic same-residue PM5 semantics. The protein consequence p.(Q79_W80delinsKG) involves a dual-residue change, and the automated system could not resolve it to a single-residue missense comparator. No same-residue candidate variants were identified in ClinVar. Details ▾Hide ▴
Evidence considered
- PM5 mode: unknown
- eligible_for_classic_pm5_search: false
- 0 same-residue candidates identified in ClinVar
Sources
pm5_candidates
BP2 N/ABP2 applies to genes where loss of function is not a known disease mechanism. PVS1 gene context review found that AKT1 loss of function is a supported germline disease mechanism, so BP2 is not applicable. Details ▾Hide ▴
Evidence considered
- AKT1 LoF mechanism supported for germline disease
Sources
pvs1_gene_context
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without known function. This variant is resolved to two adjacent missense substitutions in the PH domain of AKT1, a well-established functional domain critical for membrane localization and kinase activation. Not applicable. Details ▾Hide ▴
Evidence considered
- Variant lies in PH domain
- a critical functional domain
- Not a repetitive region
- Normalized to two missense substitutions
- not a true in-frame indel
Sources
pvs1_variant_assessment
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant (p.Q79_W80delinsKG) is a dual missense change, not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Protein change: p.(Gln79_Trp80delinsLysGly)
- not synonymous
Identifiers
- Gene
- AKT1
- Transcript
- NM_001014431.1
- Coding (HGVS c.)
- NM_001014431.1:c.235_238delinsAAGG
- Protein (HGVS p.)
- NP_001014431.1:p.(Gln79_Trp80delinsLysGly)
- GRCh38
- chr14:104776708 ACTG>CCTT
- GRCh37
- chr14:105243045 ACTG>CCTT
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
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in AKT1
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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
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 REVEL and BayesDel scores are unavailable because the pipeline classified this variant as a non-SNV during prefetch, though Mutalyzer normalization reveals it consists of two adjacent substitutions (c.235C>A, c.238T>G). SpliceAI max delta score is 0.06, indicating no significant splicing impact. Insufficient computational evidence to assess deleterious protein effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.06 (no significant splice impact)
- REVEL: skipped (pipeline classification as non-SNV)
- BayesDel: skipped (pipeline classification as non-SNV)
Still missing
- REVEL/BayesDel scores could not be computed
- individual SNV scores for c.235C>A and c.238T>G may be informative if obtained manually
Sources
BP4 No multiple lines of computational evidence are available to suggest no impact on gene product. SpliceAI delta score is 0.06 (no significant splice impact), but REVEL and BayesDel scores are unavailable. SpliceAI alone is insufficient for BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.06 (no splice impact)
- REVEL/BayesDel: unavailable (pipeline classified as non-SNV)
Still missing
- No protein-level in silico scores available
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant (p.Q79_W80delinsKG) is a dual missense change, not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Protein change: p.(Gln79_Trp80delinsLysGly)
- not synonymous
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
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 0.060
Open source ↗
ClinVar
Captured ClinVar source record
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_001014431.1%3Ac.235_238de…
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/14-105243045-ACTG-CCTT?datase…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr14-104776708-ACTG-CCTT?dat…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/14-104776708-ACTG-CCTT
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001014431.1%3Ac.2…
- OncoKB ↗www.oncokb.org/gene/AKT1/Q79_W80delinsKG
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=AKT1+c.235_238delinsAAGG
- Cancer hotspots ↗www.cancerhotspots.org/
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
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. AKT1, an intracellular kinase, is altered predominantly by mutation in various cancer types including breast and endometrial cancers.
Somatic
This variant lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant lies in a statistically significant hotspot.