NM_000314.8:c.388_389insA is a frameshift insertion in PTEN exon 5 producing p.Arg130GlnfsTer50, predicted to undergo nonsense-mediated decay well 5' of the p.D375 threshold, meeting PVS1 (very strong) per the ClinGen PTEN Expert Panel PVS1 decision tree v3.2.0.1 The variant disrupts codon 130 within the PTEN catalytic motif (residues 123-130, NP_000305.3), a critical functional domain, meeting PM1 (moderate) per PTEN VCEP specifications.2 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting level per PTEN VCEP allele frequency threshold of <0.00001 (0.001%).3 No functional studies, case reports, de novo observations, or segregation data were identified for this variant in the reviewed literature. Under the PTEN VCEP classification framework, PVS1 (very strong) plus one moderate criterion (PM1) meets Rule 10 for Likely Pathogenic classification.4
PTEN
Final classification
Pathogenic
PTEN c.388_389insA · p.Arg130GlnfsTer50
PTEN
NM_000314.8:c.388_389insA is a frameshift insertion in PTEN exon 5 producing p.Arg130GlnfsTer50, predicted to undergo nonsense-mediated decay well 5' of the p.D375 threshold, meeting PVS1 (very strong) per the ClinGen PTEN Expert Panel PVS1 decision tree v3.2.0.
Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework: matched Rule3 (1 Pathogenic.Very Strong + 1 Pathogenic.Moderate + 1 Pathogenic.Supporting) with applied criteria: PVS1 very strong, PM1 moderate, PM2 supporting; maps to Pathogenic.
Classification rationale
PVS1PM1PM2
Pathogenic
PTEN c.388_389insA
PVS1 + PM1 + PM2
→
Pathogenic
Gene diagram
· NM_000314.8 · variants mapped to exon structure
PTEN
NM_000314.8
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 12 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
Frameshift insertion c.388_389insA produces a premature termination codon at p.Arg130GlnfsTer50 (p.179), which is 5' of the p.D375 (c.1121) threshold in the PTEN VCEP PVS1 decision tree. The variant is predicted to undergo nonsense-mediated decay. Assigned PVS1 (very strong) per ClinGen PTEN Expert Panel specifications v3.2.0.
Frameshift insertion in exon 5 generating a premature stop at codon 179well 5' of the p.D375 (c.1121) NMD thresholdLoF mechanism established for PTEN per CSPEC/VCEP framework
✓
PM1
moderate
Pathogenic
The variant disrupts codon 130 (p.Arg130), which lies within the PTEN VCEP-defined catalytic motif spanning residues 123-130 (NP_000305.3). This frameshift insertion removes the critical phosphatase catalytic domain function. Additionally, the residue lies within a statistically significant cancer hotspot (cancerhotspots.org).
Residue 130 is the terminal residue of the VCEP-defined catalytic motif 123-130 (NP_000305.3)Frameshift at this position completely disrupts the phosphatase catalytic coreResidue is in a statistically significant cancer hotspot
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, satisfying the PTEN VCEP PM2 threshold of allele frequency <0.00001 (0.001%). Per VCEP specification, PM2 is applied at supporting evidence level.
Absent from gnomAD v2.1 (0 alleles)Absent from gnomAD v4.1 (0 alleles)Absent from gnomAD-Canada v1.0 (0 alleles)
Assessed · not applied
Pathogenic
PS2
No de novo observation with confirmed paternity and maternity has been identified for this variant in the available evidence.
PS3
No variant-specific functional assay data is available for NM_000314.8:c.388_389insA.
PS4
No proband counts or case-control data are available for this variant.
PM6
No assumed de novo observation has been reported for this variant.
PP1
No co-segregation data are available for this variant.
Benign
BA1
The variant is absent from gnomAD (allele frequency 0).
BS1
The variant is absent from gnomAD.
BS2
No homozygous observation in a healthy or PHTS-unaffected individual has been reported for this variant.
BS3
No well-established functional studies demonstrate a benign effect for this variant.
BS4
No lack-of-segregation data are available for this variant.
BP2
No observation of this variant in trans with a pathogenic or likely pathogenic PTEN variant, and no observations in cis with different P/LP PTEN variants have been reported.
BP5
No observation of this variant in a case with an alternate molecular basis for disease has been reported.
N/A · 12
PS1 · PM4 · PM5 · PP2 · PP3 · PP4 · PP5 · BP1 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
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 = 0.01).
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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 · 2 PMIDs not cited in assessment