NM_000314.8:c.389_405delinsTAACTGGTGTAATGATG is an in-frame deletion-insertion in exon 5 of PTEN, resulting in substitution of six residues (p.Arg130_Ile135delinsLeuThrGlyValMetMet). Residue Arg130 is the terminal residue of the P-loop/phosphatase core catalytic motif (NP_000305.3 residues 123-130), a critical functional domain defined by the ClinGen PTEN Expert Panel.1 The variant is absent from gnomAD v2.1 and v4.1 population databases, satisfying PM2 at supporting strength per PTEN VCEP specifications.2 The variant alters the P-loop catalytic motif, satisfying PM1 at moderate strength per PTEN VCEP (catalytic motifs defined as residues 90-94, 123-130, 166-168). As an in-frame deletion-insertion impacting a catalytic motif residue, PM4 also applies at moderate strength per PTEN VCEP specification.3 No variant-specific functional, segregation, de novo, or case-level evidence is available. Four publications provided in the literature packet (PMID:10866302, PMID:32350270, PMID:32366478, PMID:9467011) do not mention this variant. The Mighell et al. 2018 saturation mutagenesis assay (mmc2.xlsx) covers missense variants only and does not include in-frame indels.4 Per PTEN VCEP combination rules, two moderate criteria (PM1, PM4) and one supporting criterion (PM2_Supporting) are insufficient to reach Likely Pathogenic classification. The variant is classified as a Variant of Uncertain Significance (VUS).5
PTEN
Final classification
VUS
PTEN c.389_405delinsTAACTGGTGTAATGATG · p.Arg130_Ile135delinsLeuThrGlyValMetMet
PTEN
NM_000314.8:c.389_405delinsTAACTGGTGTAATGATG is an in-frame deletion-insertion in exon 5 of PTEN, resulting in substitution of six residues (p.Arg130_Ile135delinsLeuThrGlyValMetMet). Residue Arg130 is the terminal residue of the P-loop/phosphatase core catalytic motif (NP_000305.3 residues 123-130), a critical functional domain defined by the ClinGen PTEN Expert Panel.
ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.2 v3.2 criteria-combination framework was evaluated deterministically with applied criteria: PM1 moderate, PM2 supporting, PM4 moderate; no rule matched the adjudicated criteria.
Classification rationale
PM1PM2PM4
VUS
PTEN c.389_405delinsTAACTGGTGTAATGATG
PM1 + PM2 + PM4
→
VUS
Gene diagram
· NM_000314.8 · variants mapped to exon structure
PTEN
NM_000314.8
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 15 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM1
moderate
Pathogenic
This variant alters residues 130-135 of NP_000305.3. Residue 130 (Arg130) is the terminal residue of the P-loop/phosphatase core catalytic motif defined by the PTEN VCEP as residues 123-130. The variant replaces Arg130 with Leu, directly disrupting a critical catalytic domain.
Variant alters residue 130 within the P-loop catalytic motif (residues 123-130 per PTEN VCEP PM1 specification). Cancer Hotspots confirms this region is a statistically significant mutational hotspot.
✓
PM2
supporting
Pathogenic
The variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes), meeting the PTEN VCEP PM2_Supporting threshold of allele frequency <0.00001 (0.001%).
Absent from gnomAD v2.1 (0 alleles). Absent from gnomAD v4.1 (0 alleles).
✓
PM4
moderate
Pathogenic
NM_000314.8:c.389_405delinsTAACTGGTGTAATGATG is an in-frame deletion-insertion that alters residues 130-135, including residue Arg130 which lies within the P-loop catalytic motif (residues 123-130). Per PTEN VCEP specification, PM4 applies to in-frame insertions or deletions impacting at least one residue in a catalytic motif specified under PM1.
In-frame deletion-insertion of 6 residues (p.Arg130_Ile135delinsLeuThrGlyValMetMet) impacting the catalytic P-loop motif at residue 130.
Assessed · not applied
Pathogenic
PVS1
PTEN VCEP PVS1 decision tree applies to nonsense, frameshift, and canonical splice site variants.
PS1
No previously established pathogenic variant with the same amino acid change (p.Arg130_Ile135delinsLeuThrGlyValMetMet) has been identified.
PS2
No de novo observation has been reported for this variant.
PS3
No variant-specific functional data is available.
PS4
No proband or case-level data is available to calculate a specificity score or assess prevalence in affected individuals.
PM6
No de novo observation (assumed or confirmed) has been reported for this variant in any proband with PHTS or related phenotype.
PP1
No co-segregation data is available.
PP3
PTEN VCEP PP3 applies to missense variants with REVEL score >0.7 or splicing variants with concordant in silico predictions.
Benign
BA1
The variant is absent from gnomAD.
BS1
The variant is absent from gnomAD.
BS2
No observation of this variant in the homozygous state in a healthy or PHTS-unaffected individual has been reported.
BS3
No functional studies demonstrating no damaging effect on protein function are available for this variant.
BS4
No segregation data is available to demonstrate lack of segregation in affected family members.
BP2
No observation of this variant in trans with a pathogenic or likely pathogenic PTEN variant, nor three or more observations in cis/unknown phase with different pathogenic/likely pathogenic PTEN variants.
BP5
No evidence that this variant has been found in a case with an alternate molecular basis for disease.
N/A · 9
PM5 · PP2 · PP4 · PP5 · BP1 · BP3 · BP4 · BP6 · 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 = 0.03).
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. PTEN, a lipid and protein phosphatase, is one of the most frequently mutated genes in cancer.
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
9Sources
Triaged references · 4 PMIDs not cited in assessment
10866302 ↗
Functional evaluation of PTEN missense mutations using in vitro phosphoinositide phosphatase assay.
ONCOKB
32350270 ↗
Multi-model functionalization of disease-associated PTEN missense mutations identifies multiple molecular mechanisms underlying protein dysfunction.
ONCOKB
32366478 ↗
A Premalignant Cell-Based Model for Functionalization and Classification of PTEN Variants.
ONCOKB
9467011 ↗
Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation.
ONCOKB