Classification rationale

PVS1PM2 Likely Pathogenic

PTEN c.418_430del

The PTEN c.418_430del (p.Leu140AsnfsTer3; p.L140Nfs*3) 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 supports PM2 at supporting strength under the PTEN Expert Panel threshold for rarity.² This deletion causes a frameshift with premature termination after codon 140, and under the PTEN-specific PVS1 decision tree the premature stop is 5' to p.D375 (c.1121), supporting a loss-of-function effect.³ SpliceAI predicts possible splice impact with a maximum delta score of 0.28, but this alone does not meet the PTEN Expert Panel requirement for concordant computational evidence for PP3 or BP4.⁴

PVS1 + PM2 → Likely Pathogenic

1 clinvar ↗

2 cspec ↗gnomad_v2 ↗gnomad_v4 ↗

3 cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_p_v_s_1___d_e_c_i_s_i_o_n_t_r_e_e___p_t_e_n

4 cspec ↗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 · 16 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 predicted to cause p.(Leu140AsnfsTer3) [p.(L140Nfs*3)]. Under the PTEN-specific PVS1 decision tree, a nonsense or frameshift variant at or 5' to p.D375 (c.1121) in biologically relevant transcript NM_000314.8 meets PVS1 at very strong strength; c.418_430del is well 5' to this threshold and is consistent with a loss-of-function effect in PTEN.

NM_000314.8:c.418_430del causes NP_000305.3:p.(Leu140AsnfsTer3) / p.(L140Nfs*3).PTEN loss of function is an established disease mechanism in the PTEN Expert Panel framework.PTEN PVS1 decision tree assigns PVS1 to frameshift variants at or 5' to p.D375 (c.1121).

cspec ↗

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1. This observed allele frequency of 0 is below the PTEN Expert Panel PM2_Supporting threshold of <0.00001 (0.001%), with no subpopulation evidence exceeding the <0.00002 (0.002%) requirement, so PM2_Supporting is met.

Absent from gnomAD v2.1.Absent from gnomAD v4.1.PTEN PM2 is applied at supporting strength when allele frequency is <0.00001 and subpopulation frequency is <0.00002.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 4 not met · 12 not assessed

Pathogenic

PS2 No confirmed de novo occurrence in an affected individual was identified, so PS2 is not assessed.

PS3 No well-established functional study specific to this deletion was identified.

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

PM1 PM1 is specified for variants affecting PTEN catalytic motifs at residues 90-94, 123-130, or 166-168.

PM4 PM4 is specified for in-frame insertions or deletions affecting a catalytic motif or for stop-loss variants causing protein extension.

PM6 No assumed de novo occurrence in a patient with PTEN-related disease and no family history was identified, so PM6 is not assessed.

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

PP3 SpliceAI predicts a possible splice effect with a maximum delta score of 0.28, but the PTEN Expert Panel requires concordant splicing prediction evidence for PP3 and this variant is already established as a truncating frameshift under PVS1.

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele frequency of 0 is below the PTEN Expert Panel BA1 threshold of >0.00056 (0.056%).

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele frequency of 0 is below both the PTEN Expert Panel BS1 supporting range of 0.0000043 to 0.000043 and strong range of 0.000043 to 0.00056.

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

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

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

BP2 No phase data showing this variant in trans with a pathogenic PTEN variant, or repeated cis/phase-unknown observations with different pathogenic PTEN variants, were identified.

BP4 SpliceAI predicts a possible splice effect with a maximum delta score of 0.28, which is above the benign SpliceAI range of 0 to 0.2 specified by the PTEN Expert Panel, and no concordant benign splicing evidence was identified.

BP5 No alternate highly penetrant molecular explanation with clearly non-overlapping PTEN-related clinical features was identified, so BP5 is not assessed.

N/A · 10 PS1 · PM3 · PM5 · PP2 · PP4 · PP5 · BP1 · BP3 · 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 possible splice impact for this variant (max delta score = 0.28).

SpliceAI ↗

Functional Likely Oncogenic

OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant lies 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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