Classification rationale

PVS1PM2 Likely Pathogenic

PTEN c.890_899del

The PTEN c.890_899del (p.(Asp297AlafsTer7), p.(D297Afs*7)) 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, which is below the PTEN Expert Panel PM2_Supporting threshold of 0.00001 (0.001%).² This deletion causes a frameshift with premature termination, and under the PTEN-specific PVS1 decision tree a stop/disruption at or 5' to p.D375 (c.1121) in NM_000314.8 supports PVS1.³ SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.02; however, computational missense or splice criteria are not the primary basis for interpreting this truncating deletion.⁴

PVS1 + PM2 → Likely Pathogenic

1 clinvar ↗

2 cspec ↗gnomad_v2 ↗gnomad_v4 ↗

3 cspec ↗vcep_pvs1_decisiontree_ptenpvs1_gene_contextpvs1_variant_assessment

4 spliceai ↗cspec ↗

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.890_899del, predicted to result in p.(Asp297AlafsTer7) / p.(D297Afs*7). Under the PTEN-specific PVS1 decision tree, truncating variants with the stop/disruption at or 5' to p.D375 (c.1121) in the biologically relevant transcript NM_000314.8 meet PVS1; this variant is upstream of that threshold and PTEN loss of function is an established disease mechanism.

Frameshift consequence p.(Asp297AlafsTer7) / p.(D297Afs*7)PTEN-specific PVS1 threshold at p.D375 (c.1121)PTEN loss of function supported as disease mechanism

cspec ↗

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1. The PTEN Expert Panel PM2 threshold is allele frequency below 0.00001 (0.001%), with subpopulation allowance below 0.00002 (0.002%) if multiple alleles are present; the observed frequency is therefore below threshold and supports PM2 at supporting strength.

Absent from gnomAD v2.1Absent from gnomAD v4.1PTEN PM2_Supporting threshold <0.00001

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

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

Pathogenic

PS2 No confirmed de novo occurrence with maternity and paternity established was identified for this variant, so PS2 is not assessed.

PS3 No variant-specific functional study demonstrating a damaging effect was identified for this deletion.

PS4 No affected-case series, specificity score, or case-control enrichment data were identified for this variant, so PS4 is not assessed.

PM1 This variant affects residue 297, which is outside the PTEN Expert Panel catalytic motif residues 90-94, 123-130, and 166-168 defined for PM1.

PM6 No presumed de novo occurrence was identified for this variant, so PM6 is not assessed.

PP1 No segregation data were identified for this variant, so PP1 is not assessed.

Benign

BA1 This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, so it does not meet the PTEN BA1 stand-alone benign threshold of filtering allele frequency greater than 0.00056 (0.056%).

BS1 This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, so it does not meet the PTEN BS1 thresholds of 0.0000043 to 0.000043 for supporting evidence or 0.000043 to 0.00056 for strong evidence.

BS2 No observations of this variant in a healthy or PTEN-hamartoma-tumor-syndrome-unaffected homozygous individual were identified, so BS2 is not assessed.

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

BS4 No lack-of-segregation data were identified for this variant, so BS4 is not assessed.

BP2 No phase data were identified showing this variant in trans with a pathogenic PTEN variant or in cis/phase-unknown with multiple pathogenic PTEN variants, so BP2 is not assessed.

BP5 No evidence was identified that this variant was found in a case with an alternate highly penetrant molecular explanation and no overlap with PTEN-related disease, so BP5 is not assessed.

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 = 0.02).

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

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

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