Classification rationale

PVS1PM2 Likely Pathogenic

PTEN c.449_456del

The PTEN c.449_456del (p.Glu150GlyfsTer27) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing it below the PTEN Expert Panel PM2 population threshold of 0.001%.² This deletion is predicted to cause a frameshift with premature protein truncation, and under the PTEN-specific PVS1 decision tree its position 5' of c.1121 (p.D375) supports loss of function; SpliceAI does not predict an additional splice effect (maximum delta score 0.01).³

PVS1 + PM2 → Likely Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 vcep_pvs1_decisiontree_ptenpvs1_variant_assessmentspliceai ↗

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 · 2 applied · 13 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 · 2

Strength Supporting Moderate Strong Very strong

PVS1 very strong Pathogenic

This variant is a frameshift deletion in PTEN, NM_000314.8:c.449_456del, predicted to cause p.(Glu150GlyfsTer27). It occurs in exon 5 of the biologically relevant transcript and introduces a premature termination codon well 5' of the PTEN-specific c.1121 (p.D375) threshold, which meets the PTEN Expert Panel PVS1 decision tree for full-strength PVS1.

Frameshift consequence p.(Glu150GlyfsTer27)Variant maps to exon 5PTEN-specific PVS1 threshold at c.1121/p.D375

cspec ↗

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1 and gnomAD v4.1. Its observed population frequency is therefore below the PTEN Expert Panel PM2 threshold of 0.001% and supports PM2 at the supporting level.

Absent from gnomAD v2.1Absent from gnomAD v4.1PM2 threshold <0.001%

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 3 not met · 10 not assessed

Pathogenic

PS2 No confirmed de novo observation with documented maternity and paternity testing was identified for this variant, so PS2 is not met from the available evidence.

PS3 No variant-specific functional assay or RNA study was identified for this frameshift deletion.

PS4 No case series, prevalence comparison, or PTEN-specific proband scoring data were identified for this exact variant, so PS4 cannot be applied from the available evidence.

PM1 This variant affects codon 150.

PM6 No assumed de novo observation without parental confirmation was identified for this variant, so PM6 cannot be applied from the available evidence.

PP1 No segregation data were identified for this variant, so PP1 cannot be applied.

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its population frequency is below the PTEN BA1 threshold of 0.056% and BA1 is not met.

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its population frequency is below the PTEN BS1 thresholds of 0.00043% for supporting and 0.0043% for strong evidence.

BS2 No observations of this variant in healthy or PTEN hamartoma tumor syndrome-unaffected homozygous individuals were identified, so BS2 cannot be applied.

BS3 No well-established functional study showing no damaging effect was identified for this variant.

BS4 No lack-of-segregation evidence was identified for this variant, so BS4 cannot be applied.

BP2 No phase-resolved co-occurrence with another pathogenic or likely pathogenic PTEN variant was identified, so BP2 cannot be applied.

BP5 No evidence was identified that this variant was found in an individual with a distinct alternate molecular diagnosis and non-overlapping clinical features, so BP5 cannot be applied.

N/A · 13 PS1 · PM3 · 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.

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 v4 ↗ gnomAD v2 ↗

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 Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

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

Check your email

Reset your password

Enter an access code

Your allowance