Classification rationale

PVS1PM2 Likely Pathogenic

PTEN c.700_701del frameshift

NM_000314.8:c.700_701del is a frameshift deletion in PTEN exon 7 producing p.Arg234GlyfsTer8, a premature termination codon predicted to undergo nonsense-mediated decay at or 5' to the p.D375 (c.1121) threshold, meeting PVS1 at very-strong strength per the PTEN expert panel decision tree.¹ The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength (<0.001% allele frequency).² The variant is absent from ClinVar; no functional, de novo, segregation, or case-level evidence is available to support or refute additional criteria.³ Under the PTEN VCEP combination rules, a single PVS1 (very strong) criterion is sufficient for a Pathogenic classification (Rule 1, Condition 1).⁴

PVS1 + PM2 → Likely Pathogenic

1 vcep_pvs1_decisiontree_ptencspec ↗

2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

3 clinvar ↗

4 final_classification_framework

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

PTEN NM_000314.8

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 15 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

Frameshift deletion (NM_000314.8:c.700_701del, p.Arg234GlyfsTer8) introduces a premature termination codon in exon 7 at approximately p.241, 5' to the p.D375 (c.1121) NMD threshold, and is predicted to undergo nonsense-mediated decay in the biologically relevant transcript NM_000314.8. PTEN loss of function is an established mechanism of PTEN hamartoma tumor syndrome; per the PTEN PVS1 decision tree this is assigned full-strength PVS1.

Two-nucleotide frameshift deletion in exon 7 (c.635-801)Premature termination codon at p.241 (Arg234GlyfsTer8)5' to p.D375 (c.1121) NMD cutoff

cspec ↗

✓

PM2 supporting Pathogenic

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, satisfying the PTEN VCEP PM2_Supporting threshold (allele frequency <0.001%).

Absent from gnomAD v2.1Absent from gnomAD v4.1Absent from gnomAD-Canada v1.0

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Assessed · not applied · 15 not met · 0 not assessed

Pathogenic

PS1 No previously established pathogenic variant with the same amino acid change (p.Arg234GlyfsTer8) was identified, and the variant is absent from ClinVar, so PS1 cannot be applied.

PS2 No de novo observation (with confirmed maternity and paternity) for this variant has been reported.

PS3 No variant-specific experimental functional data exist.

PS4 No proband or affected-individual counts are available; the variant is absent from ClinVar and no case-control data exist.

PM1 The frameshift occurs at Arg234 within the C2 domain; the PTEN VCEP-defined catalytic motifs (WPD loop 90-94, P-loop 123-130, TI-loop 166-168) lie N-terminal to this position and are preserved in the truncated protein.

PM6 No assumed de novo observation for this variant has been reported.

PP1 No co-segregation data with disease in affected family members are available for this variant.

PP3 PP3 (PTEN VCEP) requires REVEL >0.7 for missense variants or SpliceAI/VarSeak splicing concordance for splicing variants.

Benign

BA1 The variant is absent from gnomAD, far below the BA1 stand-alone threshold (filtering allele frequency >0.056%).

BS1 The variant is absent from gnomAD, below the BS1 allele-frequency thresholds.

BS2 No observation in the homozygous state in a healthy or PHTS-unaffected individual has been reported.

BS3 No functional study demonstrating no damaging effect exists for this variant.

BS4 No lack-of-segregation data in affected family members are available.

BP2 No observation in trans with a pathogenic/likely pathogenic PTEN variant, nor three observations in cis/unknown phase with different pathogenic PTEN variants, has been reported.

BP5 No case with an alternate molecular basis for disease has been reported for this variant.

N/A · 11 PM3 · PM4 · PM5 · PP2 · 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

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 = 0.03).

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 previously been reported in somatic cancers (COSMIC; COSV64299636, n = 1 times).

Hotspots

This variant does not lie 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