Classification rationale

PVS1PM1PM2 Pathogenic

PTEN c.387dup frameshift · exon 5

Pathogenic: c.387dup causes a p.Arg130 frameshift upstream of the PTEN NMD threshold, meeting PVS1 very strong. Pathogenic: the frameshift begins within the PTEN catalytic motif at residues 123-130, meeting PM1 moderate. Pathogenic: the variant is absent from gnomAD v2.1 and v4.1, meeting PM2 supporting.

PVS1 + PM1 + PM2 → Pathogenic

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.

Gene diagram · NM_000314.8 · variants mapped to exon structure

PTEN NM_000314.8

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 10 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

PVS1 very strong Pathogenic

Met, very strong: the p.Arg130 frameshift is 5' of PTEN p.D375 (c.1121), so the decision tree assigns this NM_000314.8 variant full PVS1 for predicted NMD.

The normalized variant is NM_000314.8:c.387dup with protein consequences NP_000305.3:p.(Arg130ThrfsTer50) and p.(R130Tfs*50).The case evidence classifies c.387dup as a frameshift and identifies NM_000314.8 as the governing PTEN transcript.The PTEN PVS1 decision tree states that a frameshift with a stop codon or disruption at or 5' to p.D375 (c.1121), in a biologically relevant transcript and predicted to undergo NMD, receives PVS1.

cspec ↗

PM1 moderate review Pathogenic

Met, moderate: the frameshift starts at Arg130, within the PTEN VCEP catalytic-motif interval 123-130 for PM1.

The PTEN VCEP PM1 rule defines critical catalytic motifs at residues 90-94, 123-130, and 166-168 on NP_000305.3.The variant protein consequence is p.(Arg130ThrfsTer50), so the affected starting residue is Arg130 and lies within the specified 123-130 interval.No PTEN entry is present under vcep_materials.json domain_tables; the explicit PTEN VCEP PM1 residue list was therefore checked directly and includes residue 130.

cspec ↗

PM2 supporting Pathogenic

Met at Supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the PTEN PM2 requirement of frequency <0.00001.

The PTEN VCEP defines PM2 Supporting as absence or allele frequency <0.00001 (0.001%) in gnomAD, with a <0.00002 subpopulation condition when multiple alleles are present.gnomAD v2.1 reports the variant as absent.gnomAD v4.1 reports the variant as absent; the observed frequency is 0, below the PTEN PM2 threshold.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 2 not met · 8 not assessed

Pathogenic

PS2 Not assessed: no documented proband phenotype, parental testing, maternity/paternity confirmation, or de novo observation is available for this variant.

PS4 Not assessed: no case-control odds ratio or PTEN phenotype-specific proband score is available to compare with the VCEP PS4 thresholds.

PM6 Not assessed: no specific de novo report, affected proband phenotype, family history, or parental-testing information is documented for this variant.

PP1 Not assessed: no affected relatives, segregation results, family structure, or meiosis count is documented for this variant.

Benign

BA1 Not met: the variant is absent from gnomAD v2.1 and v4.1, with frequency 0 versus the PTEN BA1 threshold >0.00056.

BS1 Not met: the variant is absent from gnomAD v2.1 and v4.1, with frequency 0 below the PTEN BS1 Supporting lower bound of 0.0000043.

BS2 Not assessed: gnomAD reports no observations of the variant, so no confirmed healthy homozygote is available for the PTEN BS2 requirement.

BS4 Not assessed: no affected-family testing or documented non-segregation observation is available for this variant.

BP2 Not assessed: no qualifying trans observation or three cis/phase-unknown observations with different pathogenic PTEN variants are documented.

BP5 Not assessed: no qualifying alternate molecular diagnosis, two-case minimum, or non-overlapping PTEN history is documented for BP5.

N/A · 15 PS1 · PS3 · PM3 · PM4 · PM5 · PP2 · PP3 · PP4 · PP5 · BS3 · 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

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

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.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 2 PMIDs not cited in assessment

11237521 ↗ PTEN: life as a tumor suppressor. ONCOKB

17218262 ↗ Essential role for nuclear PTEN in maintaining chromosomal integrity. ONCOKB

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