NM_001014431.1:c.235_238delCAGTinsAAGG

AKT1 · NP_001014431.1:p.(Gln79_Trp80delinsLysGly) · NM_001014431.1

GRCh37: chr14:105243045 ACTG>CCTT · GRCh38: chr14:104776708 ACTG>CCTT

Gene: AKT1 Transcript: NM_001014431.1

Final call

VUS

PM1 moderate PM2 moderate

Variant details

Gene

AKT1

Transcript

NM_001014431.1

Protein

NP_001014431.1:p.(Gln79_Trp80delinsLysGly)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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 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).	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	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.	clinvar
PS2	Not assessed	No de novo observation with confirmed maternity and paternity has been reported for this variant.
PS3	Not assessed	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.	oncokb
PS4	Not assessed	No case-control or prevalence data comparing affected vs. unaffected individuals are available for this variant.
PS5	Not assessed	No data available on whether affected individuals carrying this variant also harbor an alternate molecular basis for disease.
PM1	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM2	Met	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 gnomad_v4 gnomad_canada
PM3	N/A	Skipped per adjudication directive.
PM4	N/A	No 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.	pvs1_variant_assessment
PM5	N/A	Unable 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.	pm5_candidates
PM6	Not assessed	No de novo observation (with or without confirmed maternity/paternity) has been reported for this variant.
PP1	Not assessed	No cosegregation data in affected families is available for this variant.
PP2	Not assessed	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.
PP3	Not assessed	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.	spliceai
PP4	Not assessed	No patient phenotype or clinical data are available to assess whether the phenotype is specific for AKT1-related disease.
PP5	Not assessed	This variant is absent from ClinVar. No reputable source (clinical diagnostic laboratory, expert panel) has reported this variant as pathogenic.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data on observation of this variant in healthy adult controls with full penetrance expected at an early age.
BS3	Not assessed	No well-established functional studies demonstrating no deleterious effect have been identified for this variant.
BS4	Not assessed	No segregation data in affected families is available to assess lack of cosegregation with disease.
BP1	Not assessed	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.	pvs1_gene_context
BP2	N/A	BP2 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.	pvs1_gene_context
BP3	N/A	BP3 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.	pvs1_variant_assessment
BP4	Not assessed	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.	spliceai
BP5	Not assessed	No data available on whether this variant has been observed in a case with an alternate molecular basis for disease.
BP6	Not assessed	This variant is absent from ClinVar. No reputable source has reported it as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This variant (p.Q79_W80delinsKG) is a dual missense change, not a synonymous variant.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.