Classification rationale

PVS1PM2 Likely Pathogenic

PTEN c.570_571delinsT

The PTEN c.570_571delinsT (p.Val191TrpfsTer8; p.V191Wfs*8) 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 VCEP PM2_Supporting population threshold of 0.001%.² This frameshift is predicted to introduce a premature stop codon after 8 altered amino acids at codon 191, and the PTEN VCEP PVS1 decision tree supports PVS1 for truncating variants at or 5' to p.D375 in the biologically relevant transcript NM_000314.8.³ SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.06.⁴

PVS1 + PM2 → Likely Pathogenic

1 clinvar ↗

2 cspec ↗gnomad_v2 ↗gnomad_v4 ↗

3 pvs1_gene_contextpvs1_variant_assessmentvcep_pvs1_decisiontree_pten

4 spliceai ↗

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, NM_000314.8:c.570_571delinsT, predicted to result in p.(Val191TrpfsTer8) [p.(V191Wfs*8)] with a premature stop codon well 5' to the PTEN VCEP p.D375 (c.1121) threshold. PTEN loss of function is an established disease mechanism, and the PTEN-specific PVS1 decision tree supports full-strength PVS1 for truncating variants in this region of the biologically relevant transcript.

Frameshift consequence p.(Val191TrpfsTer8) / p.(V191Wfs*8)PTEN VCEP PVS1 decision tree uses p.D375 (c.1121) thresholdPTEN loss of function is an established disease mechanism

cspec ↗

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1 and gnomAD v4.1. Under the PTEN VCEP specification, PM2_Supporting is met when the allele frequency is <0.001% and, if multiple alleles are present in any subpopulation, that subpopulation frequency is <0.002%; this variant is below those thresholds.

Absent from gnomAD v2.1Absent from gnomAD v4.1PTEN PM2 threshold <0.001%

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 4 not met · 9 not assessed

Pathogenic

PS2 No confirmed de novo observation with maternity and paternity confirmed was identified for this variant, so PS2 cannot be applied from the available evidence.

PS3 No variant-specific functional assay showing a damaging effect was identified for this frameshift variant.

PS4 No affected proband count, specificity score, or case-control enrichment data were identified for this variant, so PS4 cannot be applied.

PM1 This variant affects codon 191, which is outside the PTEN catalytic motif residues defined for PM1 (90-94, 123-130, and 166-168).

PM6 No assumed or confirmed de novo observation was identified for this variant, so PM6 cannot be applied from the available evidence.

PP1 No segregation data were identified for this variant, so PP1 cannot be applied.

Benign

BA1 This variant is absent from gnomAD and does not meet the PTEN BA1 population threshold of >0.056% allele frequency.

BS1 This variant is absent from gnomAD and does not meet the PTEN BS1 thresholds of 0.00043%-0.0043% for supporting evidence or 0.0043%-0.056% for strong evidence.

BS2 No homozygous observation in a healthy or PTEN hamartoma tumor syndrome-unaffected individual was identified, so BS2 is not met.

BS3 No variant-specific functional study showing no damaging effect was identified.

BS4 No nonsegregation data were identified for this variant, so BS4 cannot be applied.

BP2 No phase data were identified showing this variant in trans with a pathogenic PTEN variant or repeated cis/phase-unknown observations with different pathogenic PTEN variants, so BP2 cannot be applied.

BP5 No alternate highly penetrant molecular explanation with non-overlapping clinical features was identified, so BP5 cannot be applied.

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 = 0.06).

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

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