Classification rationale

PVS1PM2 Likely Pathogenic

PTEN c.33_54del

NM_000314.6:c.33_54del is a 22 bp deletion in exon 1 of PTEN causing a frameshift (p.Asn12MetfsTer5) predicted to undergo nonsense-mediated decay, assigned PVS1 at very strong strength under the PTEN VCEP decision tree.¹ The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting PM2 at supporting strength under PTEN VCEP specifications.² The variant is absent from ClinVar; no functional studies, segregation data, case observations, or de novo reports were identified in the reviewed literature.³ Under the PTEN VCEP combination rules (Rule20, pathogenic track), PVS1 (Very Strong) plus one Supporting criterion (PM2_Supporting) yields a final classification of Likely Pathogenic.⁴

PVS1 + PM2 → Likely Pathogenic

1 cspec ↗pvs1_gene_contextpvs1_variant_assessment

2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

3 clinvar ↗

4 cspec ↗

Gene diagram · NM_000314.6 · variants mapped to exon structure

PTEN NM_000314.6

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 14 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PVS1 very strong Pathogenic

NM_000314.6:c.33_54del is a 22 bp frameshift deletion in exon 1 producing a premature stop codon at position 16 (p.Asn12MetfsTer5), well 5' to the PTEN NMD threshold at p.D375 (c.1121). Under the PTEN VCEP PVS1 decision tree, a frameshift variant with stop codon at or 5' to p.D375 that is predicted to undergo nonsense-mediated decay in a biologically-relevant transcript is assigned PVS1 at very strong strength.

Frameshift variant introducing premature termination codon at amino acid 16 in exon 1 of 9PTEN PVS1 decision tree: stop codon at or 5' to p.D375 (c.1121) with predicted NMD → PVS1Loss of function is an established disease mechanism for PTEN per CSPEC/VCEP framework

cspec ↗

✓

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. Under PTEN VCEP specifications, PM2 is applied at supporting strength when a variant is absent from population databases (allele frequency < 0.00001 / 0.001%).

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

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Assessed · not applied

Pathogenic

PS2 No de novo observation of this variant has been reported.

PS3 PTEN VCEP PS3 criteria apply to RNA/mini-gene splicing assays (Strong) or phosphatase activity via Mighell et al.

PS4 PTEN VCEP PS4 requires proband specificity scores.

PM1 PTEN VCEP defines PM1 for residues in catalytic motifs: WPD loop (90-94), P-loop (123-130), and TI-loop (166-168).

PM6 No assumed de novo observations have been reported for this variant.

PP1 No co-segregation data are available for this variant.

PP3 PTEN VCEP PP3 applies to splicing variants with SpliceAI/VarSeak concordance or missense variants with REVEL > 0.7.

Benign

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

BS1 PTEN VCEP BS1 requires gnomAD filtering allele frequency ≥ 0.0000043 (0.00043%) for supporting or ≥ 0.000043 (0.0043%) for strong.

BS2 PTEN VCEP BS2 requires observation in the homozygous state in a healthy or PHTS-unaffected individual.

BS3 PTEN VCEP BS3 applies to intronic/synonymous variants showing no splicing impact (Strong) or phosphatase activity > 0 via Mighell et al.

BS4 PTEN VCEP BS4 requires lack of segregation in affected family members.

BP2 PTEN VCEP BP2 requires observation in trans with a pathogenic/likely pathogenic PTEN variant or at least three observations in cis/unknown phase with different P/LP variants.

BP5 PTEN VCEP BP5 requires at least two cases where the variant is found with an alternate molecular basis for disease.

N/A · 12 PS1 · 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 = 0.13).

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

Re-run this variant?