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.1 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%.2 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).3 PVS1 is not applicable: Mutalyzer normalization resolves the variant to two adjacent missense substitutions (p.Q79K, p.W80G) rather than a null variant.4 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.5
AKT1
Final classification
VUS
AKT1 c.235_238delinsAAGG · p.Gln79_Trp80delinsLysGly
AKT1
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.
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.
Classification rationale
PM1PM2
VUS
AKT1 c.235_238delinsAAGG
PM1 + PM2
→
VUS
3
generic_acmg_combination_rules
4
pvs1_variant_assessmentpvs1_generic_framework ↗
Gene diagram
· NM_001014431.1 · variants mapped to exon structure
AKT1
NM_001014431.1
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 19 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM1
moderate
Pathogenic
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.
CancerHotspots: residues Q79 and W80 lie within a statistically significant hotspotPH domain (residues ~1-110) is a critical functional domain for membrane recruitmentAbsent from gnomAD
✓
PM2
moderate
Pathogenic
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.
gnomAD v2.1: absent (AF = 0.00%)gnomAD v4.1: absent (AF = 0.00%)gnomAD-Canada v1.0: absent (AF = 0.00%)
Assessed · not applied
Pathogenic
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.
PS2
No de novo observation with confirmed maternity and paternity has been reported for this variant.
PS3
No variant-specific functional studies were identified.
PS4
No case-control or prevalence data comparing affected vs.
PM6
No de novo observation (with or without confirmed maternity/paternity) has been reported for this variant.
PP1
No cosegregation data in affected families is available for this variant.
PP2
HCI prior score for AKT1 is not available (gene not supported by the HCI prior database).
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).
PP4
No patient phenotype or clinical data are available to assess whether the phenotype is specific for AKT1-related disease.
PP5
This variant is absent from ClinVar.
Benign
BA1
Allele frequency is 0.00% in gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
Allele frequency is 0.00% in gnomAD v2.1, v4.1, and gnomAD-Canada.
BS2
No data on observation of this variant in healthy adult controls with full penetrance expected at an early age.
BS3
No well-established functional studies demonstrating no deleterious effect have been identified for this variant.
BS4
No segregation data in affected families is available to assess lack of cosegregation with disease.
BP1
AKT1 has both gain-of-function (activating missense variants such as E17K) and loss-of-function germline disease mechanisms reported.
BP4
No multiple lines of computational evidence are available to suggest no impact on gene product.
BP5
No data available on whether this variant has been observed in a case with an alternate molecular basis for disease.
BP6
This variant is absent from ClinVar.
N/A · 7
PVS1 · PM3 · PM4 · PM5 · BP2 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).
Functional
Likely Oncogenic
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.
COSMIC
Cancer hotspots
Somatic evidence
Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant lies in a statistically significant hotspot.
Sources & reference links