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PTEN
Final classification
Likely Pathogenic
PVS1PM2
PTEN
c.775_781del
p.His259ArgfsTer5
frameshift · exon 7
Gene context NCBI Gene ↗ OncoKB ↗

PTEN is a tumor suppressor gene that encodes a phosphatase converting the lipid messenger PIP3 back to PIP2 at the cell membrane, thereby restraining the AKT/mTOR signaling pathway that drives cell growth, proliferation, and survival. It is one of the most frequently mutated genes across many types of human cancer, and its loss promotes unchecked cell growth, survival, and genomic instability, partly through impaired DNA repair. Germline loss-of-function variants in PTEN cause Cowden syndrome, an inherited cancer predisposition disorder associated with elevated risk of breast and thyroid cancer.

This variant

PTEN is a tumor suppressor whose germline loss-of-function variants cause Cowden syndrome, an inherited cancer-predisposition disorder. This frameshift is predicted to trigger nonsense-mediated decay and eliminate PTEN function, so a Likely Pathogenic classification aligns with the gene's established disease mechanism.

Transcript
NM_000314.8
HGVS · transcript:coding
NM_000314.8:c.775_781del
GRCh38
chr10:87957991 TCCACAAA>T
GRCh37
chr10:89717748 TCCACAAA>T
Basis Adjudicated criteria PVS1 (Very Strong) plus PM2 (Supporting) match ClinGen PTEN VCEP Rule 20 (PVS1 + one supporting-level code), yielding Likely Pathogenic. ▾
Adjudicated criteria PVS1 (Very Strong) plus PM2 (Supporting) match ClinGen PTEN VCEP Rule 20 (PVS1 + one supporting-level code), yielding Likely Pathogenic.
Classification rationale
PVS1PM2 Likely Pathogenic
PTEN c.775_781del frameshift · exon 7

PVS1 (Very Strong): frameshift p.(His259ArgfsTer5) truncates upstream of the PTEN NMD cutoff at c.1121, predicting nonsense-mediated decay. PM2 (Supporting): variant is absent from gnomAD v2.1 and v4.1, below the 0.001% allele-frequency threshold. Combined, PVS1 plus PM2 matches ClinGen PTEN VCEP Rule 20, supporting a classification of Likely Pathogenic.

PVS1 + PM2 → Likely Pathogenic
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
Met (Very Strong): frameshift p.(His259ArgfsTer5) truncates well before the PTEN VCEP NMD cutoff at c.1121, predicting nonsense-mediated decay.
PTEN VCEP PVS1 decision tree: frameshift variants with stop codon or disruption at or 5' to p.D375 (c.1121) in biologically-relevant transcript NM_000314.8 are assigned full PVS1.Variant truncates protein at residue ~264 (p.His259ArgfsTer5), which is at/5' of the c.1121/p.D375 cutoff, so NMD is predicted per the VCEP rule rather than escape.pvs1_gene_context.json confirms germline LoF is an established PTEN disease mechanism per official CSPEC (pvs1_gene_gate: eligible).
cspec ↗
✓
PM2 supporting Pathogenic
Met (Supporting): absent from gnomAD v2.1 and v4.1, below the PTEN 0.001% allele-frequency threshold.
gnomAD v2.1 direct-variant query (GRCh37 10-89717748-TCCACAAA-T) returned absent.gnomAD v4.1 direct-variant query (GRCh38 chr10-87957991-TCCACAAA-T) returned absent.gnomAD-Canada v1.0 direct-variant query (GRCh38 10-87957991-TCCACAAA-T) returned absent, providing concordant additional population-database evidence.
cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
Assessed · not applied · 4 not met · 10 not assessed
Pathogenic
PS2 Not assessed: no parental test results or parentage confirmation were available to establish a confirmed de novo occurrence.
PS3 Not assessed: VCEP functional-evidence rules cover only missense (Mighell assay) or splice variants, and no variant-specific functional study of this frameshift was available.
PS4 Not assessed: no affected-case observations or case-control enrichment data for this exact variant were available.
PM6 Not assessed: no parental testing or family-history data were available to document a presumed de novo occurrence.
PP1 Not assessed: no pedigree or affected-relative genotype data were available to evaluate co-segregation.
PP5 Not met: the exact variant is absent from ClinVar, so no expert-panel pathogenic assertion exists to support PP5.
Benign
BA1 Not met: absent from gnomAD v2.1 and v4.1, far below the PTEN BA1 threshold of >0.056% allele frequency.
BS1 Not met: absent from gnomAD v2.1 and v4.1, below the PTEN BS1 frequency ranges.
BS2 Not assessed: no homozygous observations were available to evaluate presence in healthy individuals.
BS3 Not assessed: VCEP BS3 rules (Mighell missense assay, splice assays) do not cover frameshifts, and no variant-specific benign functional study was available.
BS4 Not assessed: no variant-negative affected relatives were documented, so non-segregation could not be evaluated.
BP2 Not assessed: no second pathogenic PTEN variant or phase data were available to evaluate.
BP5 Not assessed: no data documented an alternate molecular diagnosis explaining the phenotype.
BP6 Not met: the exact variant is absent from ClinVar, so no expert-panel benign assertion exists to support BP6.
N/A · 12 PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · PP3 · PP4 · BP1 · BP3 · BP4 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
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 Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
SpliceAI ↗
Functional / OncoKB screenshot
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 screenshot
COSMIC
Cancer hotspots screenshot
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
9Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
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