Classification rationale

PVS1PM2 Likely Pathogenic

PTEN c.197_203del frameshift · exon 3

PVS1 (Very Strong): 7-bp frameshift deletion (p.Lys66ThrfsTer31) truncating 5' of the p.D375 threshold, predicted to trigger nonsense-mediated decay. PM2 (Supporting): variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, below the 0.001% population-frequency threshold. PVS1 + PM2 satisfies Rule 20 of the PTEN VCEP, producing a Likely Pathogenic classification.

PVS1 + PM2 → Likely Pathogenic

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

Met (Very Strong): 7-bp frameshift deletion (p.Lys66ThrfsTer31) truncates the protein 5' of the p.D375 threshold, predicted to trigger nonsense-mediated decay.

PTEN VCEP PVS1 decision tree (PVS1_DecisionTree_PTEN.pdf) applies NMD prediction and the p.D375 (c.1121) positional threshold to null variants in NM_000314.8: stop codon/disruption at or 5' to p.D375 in the biologically-relevant transcript is assigned PVS1 (Very Strong).Case normalization data: NM_000314.8:c.197_203del produces NP_000305.3:p.(K66Tfs*31), a frameshift with premature termination at approximately codon 96, well 5' of the p.D375 (c.1121) threshold and not in the terminal exon, consistent with NMD prediction.

cspec ↗

✓

PM2 supporting Pathogenic

Met (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada, below the 0.001% population-frequency threshold.

The PTEN VCEP specifies PM2 supporting for databases present at less than 0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population; when multiple alleles are present within any subpopulation, the subpopulation allele frequency must be less than 0.00002 (0.002%).The case bundle reports the variant as absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, which is below both specified frequency thresholds and supports PM2 at supporting strength.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Assessed · not applied · 2 not met · 11 not assessed

Pathogenic

PS2 Not assessed: no proband, de novo observation, or parental-testing results were available.

PS3 Not assessed: the VCEP functional assay covers only missense variants, and no variant-specific functional study was available.

PS4 Not assessed: no case-control counts, odds ratios, or phenotype-specificity data were available for this variant.

PM6 Not assessed: no documented de novo occurrence or parental-testing results were available.

PP1 Not assessed: no affected relatives or segregation results were reported.

PP5 Not assessed: no exact-variant ClinVar expert-panel classification was available.

Benign

BA1 Not met: variant is absent from gnomAD, so the >0.056% BA1 frequency threshold is not reached.

BS1 Not met: variant is absent from gnomAD, so neither the strong nor supporting BS1 frequency interval is reached.

BS2 Not assessed: no homozygous observations in healthy or unaffected individuals were available.

BS3 Not assessed: the VCEP benign functional assay covers only missense variants, and no variant-specific study was available.

BS4 Not assessed: no family members lacking the variant were documented, so lack of segregation could not be established.

BP2 Not assessed: no cis, trans, or phase observations with pathogenic PTEN variants were available.

BP5 Not assessed: no cases with an alternate molecular basis or non-overlapping phenotype were available.

N/A · 13 PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · PP3 · PP4 · 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 = 0.04).

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