Starting

Initialising…

PTEN

Final classification

Likely Pathogenic

PTEN c.890_899del · p.Asp297AlafsTer7

PTEN

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.

Gene

PTEN

Transcript

NM_000314.8

HGVS · transcript:coding

NM_000314.8:c.890_899del

Consequence

N/A

GRCh38

chr10:87960981 GATCAAGAAAT>G

GRCh37

chr10:89720738 GATCAAGAAAT>G

Basis Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework: matched Rule20 (1 Pathogenic.Very Strong + 1 Pathogenic.Supporting) with applied criteria: PVS1 very strong, PM2 supporting; maps to Likely Pathogenic. ▾

Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework: matched Rule20 (1 Pathogenic.Very Strong + 1 Pathogenic.Supporting) with applied criteria: PVS1 very strong, PM2 supporting; maps to Likely Pathogenic.

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 ↗

Gene diagram · NM_000314.8 · variants mapped to exon structure

PTEN NM_000314.8

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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