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PTEN
Final classification
Likely Pathogenic
PVS1PM2
PTEN
c.538del
p.Tyr180ThrfsTer3
frameshift · exon 6
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

Germline loss-of-function variants in PTEN cause Cowden syndrome, an inherited cancer predisposition disorder with elevated breast and thyroid cancer risk. This frameshift, predicted to eliminate PTEN function through nonsense-mediated decay, is classified Likely Pathogenic, directly matching the loss-of-function mechanism by which this tumor suppressor drives disease.

Transcript
NM_000314.8
HGVS · transcript:coding
NM_000314.8:c.538del
GRCh38
chr10:87952162 CT>C
GRCh37
chr10:89711919 CT>C
Basis Likely Pathogenic: PVS1 (Very Strong) plus PM2 (Supporting) satisfies PTEN VCEP Rule20, requiring one Pathogenic.Very Strong and one Pathogenic.Supporting criterion. ▾
Likely Pathogenic: PVS1 (Very Strong) plus PM2 (Supporting) satisfies PTEN VCEP Rule20, requiring one Pathogenic.Very Strong and one Pathogenic.Supporting criterion.
Classification rationale
PVS1PM2 Likely Pathogenic
PTEN c.538del frameshift · exon 6

PVS1 (Very Strong): frameshift p.(Tyr180ThrfsTer3) introduces a premature stop at residue 182, upstream of the PTEN p.Asp375 threshold and predicted to trigger nonsense-mediated decay. PM2 (Supporting): variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the PTEN <0.001% population rarity requirement. Overall: Likely Pathogenic by PTEN VCEP Rule20, combining one Very Strong (PVS1) and one Supporting (PM2) pathogenic criterion.

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 · 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
Met (Very Strong): frameshift p.(Tyr180ThrfsTer3) stops translation at residue 182, upstream of the PTEN p.Asp375 threshold, with nonsense-mediated decay predicted.
Normalization on the PTEN Expert Panel's biologically relevant transcript NM_000314.8 gives p.(Tyr180ThrfsTer3) for c.538del and places the variant in exon 6.The PTEN Expert Panel PVS1 decision tree assigns PVS1 to frameshift or nonsense variants at or 5′ to p.Asp375 (c.1121) in NM_000314.8; c.538del is 5′ to this threshold.The premature stop at residue 182 occurs before downstream exon junctions, consistent with nonsense-mediated decay rather than a distal NMD-escaping truncation.
cspec ↗
✓
PM2 supporting Pathogenic
Met (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the PTEN <0.001% population frequency requirement.
ClinGen PTEN Expert Panel Specification version 3.2 defines PM2 Supporting as allele frequency <0.00001 (0.001%) in gnomAD or another large sequenced population; if multiple alleles are present in a subpopulation, that subpopulation frequency must be <0.00002 (0.002%).The normalized variant NM_000314.8:c.538del, corresponding to NC_000010.10:g.89711920del and NC_000010.11:g.87952163del, was reported absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.Because the variant is absent rather than observed at a measurable frequency, no ancestry-specific frequency exceeds the VCEP PM2 limit in the available queried datasets.
cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
Assessed · not applied · 6 not met · 10 not assessed
Pathogenic
PS2 Not assessed: no parental testing, maternity or paternity confirmation, or phenotype data documenting a de novo occurrence was available.
PS3 Not assessed: no functional assay result exists for this exact frameshift; available PTEN phosphatase data cover only missense variants.
PS4 Not assessed: no affected-case counts, phenotype-specificity scores, or case-control data for this variant were available.
PM1 Not met: residue Tyr180 lies outside the PTEN catalytic motifs (WPD 90-94, P-loop 123-130, TI-loop 166-168) and no mutational hotspot was found.
PM4 Not met: this is a frameshift, not an in-frame insertion/deletion or stop-loss variant, so PM4 does not apply.
PM6 Not assessed: no case observations or parental testing data from which a presumed de novo occurrence could be assigned were available.
PP1 Not assessed: no affected relatives carrying the variant, pedigree, or segregation data were available to evaluate co-segregation.
PP5 Not met: no ClinVar record exists for this exact variant, so no expert-panel pathogenic assertion could support it.
Benign
BA1 Not met: BA1 requires gnomAD frequency above 0.056%; the variant is absent from all queried gnomAD datasets.
BS1 Not met: BS1 requires gnomAD frequency of 0.00043% to 0.056%; the variant is absent from gnomAD.
BS2 Not assessed: no observation of the variant in the homozygous state in healthy or unaffected individuals was available.
BS3 Not assessed: no benign functional assay result exists for this exact frameshift variant.
BS4 Not assessed: no family testing or pedigree data showing lack of segregation were available.
BP2 Not assessed: no co-occurring PTEN variant, phase information, or parental testing data were available.
BP5 Not assessed: no observation of this variant alongside a qualifying alternate molecular diagnosis was available.
BP6 Not met: no ClinVar record exists for this exact variant, so no expert-panel benign assertion could support it.
N/A · 10 PS1 · PM3 · 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 = 0.03).
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