Classification rationale

PVS1PM2 Likely Pathogenic

PTEN c.951_952del

NM_000314.8:c.951_952del is a frameshift deletion in exon 8 of PTEN resulting in a premature termination codon at p.(Leu318TyrfsTer6), located 5' of the p.D375 threshold and predicted to undergo nonsense-mediated decay, satisfying PVS1 at very strong strength per the PTEN VCEP decision tree.¹ The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada across all populations, meeting PM2 at supporting strength per PTEN VCEP allele frequency threshold of < 0.001%.² No additional pathogenic or benign criteria are met. One very strong criterion (PVS1) and one supporting criterion (PM2) are applied. Per PTEN VCEP Rule 20, this combination of one very strong and one supporting criterion yields a classification of Likely Pathogenic.³

PVS1 + PM2 → Likely Pathogenic

1 cspec ↗vcep_pvs1_decisiontree_ptenpvs1_gene_contextpvs1_variant_assessment

2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗cspec ↗

3 cspec ↗

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

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PVS1 very strong Pathogenic

Frameshift variant NM_000314.8:c.951_952del introduces a premature termination codon at p.(Leu318TyrfsTer6), located at or 5' to p.D375 (c.1121) in biologically-relevant transcript NM_000314.8. The stop codon occurs ~55 nt upstream of the last exon-exon junction (exon 8/9 at c.1026/1027) and is predicted to undergo nonsense-mediated decay. Per PTEN VCEP PVS1 decision tree, this satisfies PVS1 at very strong strength.

Frameshift variant in exon 8 introduces premature stop at codon 324Stop codon is 5' of p.D375 (c.1121) positional thresholdPredicted to undergo NMD: stop ~55 nt upstream of last exon-exon junction

cspec ↗

✓

PM2 supporting Pathogenic

Variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0. Per PTEN VCEP specification, PM2 is applied at supporting strength for variants with allele frequency < 0.00001 (0.001%).

Absent from gnomAD v2.1 (AF = 0)Absent from gnomAD v4.1 (AF = 0)Absent from gnomAD-Canada v1.0 (AF = 0)

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗cspec ↗

Assessed · not applied

Pathogenic

PS1 No established pathogenic variant at the same amino acid position with the same change has been identified.

PS2 No de novo observation with confirmed parentage has been identified for this variant in any available data source.

PS3 No variant-specific functional data available.

PS4 No proband count or case-control data available.

PM1 The PTEN VCEP defines PM1 as limited to catalytic motif residues: 90-94 (WPD loop), 123-130 (P-loop), and 166-168 (TI-loop) per NP_000305.3.

PM6 No de novo observation (assumed or confirmed) has been identified for this variant in the available data.

PP1 No co-segregation data available.

PP3 PP3 per PTEN VCEP applies to splicing variants (SpliceAI + VarSeak concordance) or missense variants (REVEL > 0.7).

Benign

BA1 BA1 per PTEN VCEP requires a gnomAD filtering allele frequency > 0.00056 (0.056%).

BS1 BS1 per PTEN VCEP requires a gnomAD filtering allele frequency >= 0.0000043 (0.00043%).

BS2 BS2 requires observation of the variant in the homozygous state in a healthy or PHTS-unaffected individual.

BS3 No functional studies demonstrating a benign effect have been identified.

BS4 No segregation data demonstrating lack of segregation in affected family members are available for this variant.

BP2 No evidence that this variant has been observed in trans with a pathogenic or likely pathogenic PTEN variant, or in cis/unknown phase with at least three different pathogenic/likely pathogenic PTEN variants.

BP5 No evidence that this variant has been found in cases with an alternate molecular basis for disease.

N/A · 10 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 = 0.02).

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

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