Classification rationale

PVS1PM2 Likely Pathogenic

PTEN c.416T>G

The PTEN c.416T>G (p.(Leu139Ter)) variant has been observed in somatic cancers (COSMIC COSV64297098, n=6) and has been reported in ClinVar as pathogenic by a single submitter.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, which meets the PTEN VCEP PM2_Supporting rarity threshold of less than 0.001% allele frequency.² This variant introduces a premature stop codon at Leu139, and under the PTEN-specific PVS1 decision tree truncating variants at or 5' to p.D375 in transcript NM_000314.8 are assigned PVS1; SpliceAI predicts no significant splice effect with a maximum delta score of 0.01.³

PVS1 + PM2 → Likely Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 cspec ↗vcep_pvs1_decisiontree_ptenpvs1_variant_assessmentspliceai ↗

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 · 14 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 nonsense change, NM_000314.8:c.416T>G (p.(Leu139Ter)), predicted to truncate PTEN early in the coding sequence. Under the PTEN-specific PVS1 decision tree, truncating variants at or 5' to p.D375 (c.1121) in biologically relevant transcript NM_000314.8 are assigned PVS1, and Leu139Ter is upstream of that threshold.

Nonsense consequence p.(Leu139Ter)PTEN-specific PVS1 decision tree threshold at p.D375 (c.1121)PTEN loss of function is an established disease mechanism in the VCEP framework

cspec ↗

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1 and gnomAD v4.1. This is below the PTEN VCEP PM2 threshold of <0.00001 (0.001%) allele frequency and supports PM2_Supporting.

Absent from gnomAD v2.1Absent from gnomAD v4.1

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 4 not met · 10 not assessed

Pathogenic

PS1 No prior pathogenic variant with a different nucleotide change producing the same amino acid change was identified in the reviewed evidence, so PS1 was not applied.

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

PS3 No variant-specific functional study meeting the PTEN VCEP PS3 rules was identified for this nonsense variant.

PS4 This variant has been reported in ClinVar and in somatic cancers in COSMIC, but no countable germline proband data or case-control enrichment meeting the PTEN VCEP PS4 rules were identified.

PM1 This variant is not located in a PTEN catalytic motif defined for PM1.

PM6 No presumed de novo observation without parental confirmation was identified for this variant, so PM6 was not applied.

PP1 No segregation data were identified for this variant, so PP1 was not applied.

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the PTEN VCEP BA1 threshold of >0.00056 (0.056%).

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the PTEN VCEP BS1 thresholds of 0.0000043-0.00056 allele frequency.

BS2 No homozygous observation in a healthy or PTEN hamartoma tumor syndrome-unaffected individual was identified for this variant, so BS2 was not applied.

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

BS4 No lack-of-segregation evidence was identified for this variant, so BS4 was not applied.

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 was not applied.

BP5 No alternate highly penetrant molecular explanation with a non-overlapping phenotype was identified, so BP5 was not applied.

N/A · 12 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 has been reported in ClinVar as Pathogenic (1 clinical laboratory). (ClinVarID = 427590)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.652534.

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 previously been reported in somatic cancers (COSMIC; COSV64297098, n = 6 times).

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 · 8 PMIDs not cited in assessment

11237521 ↗ PTEN: life as a tumor suppressor. ONCOKB

17218262 ↗ Essential role for nuclear PTEN in maintaining chromosomal integrity. ONCOKB

25645574 ↗ ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. CLINVAR

17392385 ↗ American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CLINVAR

20301661 ↗ PTEN Hamartoma Tumor Syndrome. CLINVAR

23519317 ↗ Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. CLINVAR

23788249 ↗ ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. CLINVAR

25190698 ↗ Genetic/familial high-risk assessment: breast and ovarian, version 1.2014. CLINVAR

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