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PTEN
Final classification
VUS
PM2PP2PP3BS3
PTEN
c.155A>T
p.Asp52Val
missense · exon 2
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 causes Cowden syndrome, an inherited predisposition to breast and thyroid cancer. This c.155A>T (p.Asp52Val) variant is a VUS: absent from population databases and predicted damaging by REVEL (0.95), but with measured retained phosphatase activity. Whether it impairs PTEN's tumor-suppressor function and alters cancer risk remains unresolved.

Transcript
NM_000314.8
HGVS · transcript:coding
NM_000314.8:c.155A>T
GRCh38
chr10:87894100 A>T
GRCh37
chr10:89653857 A>T
Basis PTEN Expert Panel v3.2 rules applied: PM2, PP2, PP3, and BS3, each supporting; no pathogenic, likely pathogenic, benign, or likely benign rule is satisfied, so the classification is VUS. ▾
PTEN Expert Panel v3.2 rules applied: PM2, PP2, PP3, and BS3, each supporting; no pathogenic, likely pathogenic, benign, or likely benign rule is satisfied, so the classification is VUS.
Classification rationale
PM2PP2PP3 BS3 VUS
PTEN c.155A>T missense · exon 2

PM2 (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada. PP2 (Supporting): missense variant in a gene where missense is a common disease mechanism with a low benign missense rate. PP3 (Supporting): REVEL 0.95 exceeds the >0.7 threshold. BS3 (Supporting): measured functional score 0.11 indicates retained phosphatase activity. Overall: VUS under the PTEN Expert Panel v3.2 combination rule, as no pathogenic or benign criterion reaches the required strength.

PM2 + PP2 + PP3 + BS3 → VUS
Gene diagram · NM_000314.8 · variants mapped to exon structure
PTEN NM_000314.8
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 19 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 · 4
Strength Supporting Moderate Strong Very strong
✓
PM2 supporting Pathogenic
Met (supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the <0.001% allele-frequency requirement.
ClinGen PTEN Expert Panel Specification v3.2 permits PM2 Supporting when the variant is absent or present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population; if multiple alleles occur in a subpopulation, that subpopulation frequency must be <0.00002 (0.002%).The case bundle reports NM_000314.8:c.155A>T as absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.
cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
✓
PP2 supporting Pathogenic
Met (supporting): missense variant in PTEN, where missense is a common disease mechanism and benign missense variation is rare.
The normalized consequence is NP_000305.3:p.(Asp52Val), a missense change.The PTEN VCEP Version 3.2 framework lists PP2 as applicable at Supporting strength and uses the rule for genes with a low rate of benign missense variation in which missense variants are a common disease mechanism.This assessment uses the governing PTEN-specific framework rather than a variant-level classification from another source.
cspec ↗
✓
PP3 supporting Pathogenic
Met (supporting): REVEL score 0.95 exceeds the >0.7 threshold.
ClinGen PTEN Expert Panel Specifications v3.2 direct PP3 instruction for missense variants: REVEL score >0.7 supports PP3 at supporting strength.The variant-specific REVEL score is 0.95.
cspec ↗
✓
BS3 supporting Benign
Met (supporting): measured functional score 0.11 indicates retained phosphatase activity (>0 per Mighell et al. 2018).
The PTEN VCEP Version 3.2 specification states that BS3_Supporting applies for phosphatase activity >0 per Mighell et al. 2018 (PMID:29706350).The VCEP Table S2 exact-match row for D52V/Asp52Val reports Cum_score 0.113827986, which is >0, with High_conf=True and High_conf_nature='Pass SE Filter'.The available VCEP assay result is high-confidence by the reported standard-error/concordance filtering flag; no additional orthogonal assay is required by the cited PTEN-specific BS3_Supporting rule.
cspec ↗
Assessed · not applied · 7 not met · 12 not assessed
Pathogenic
PVS1 Not met: c.155A>T is a missense substitution, p.(Asp52Val), not a null variant, so PVS1 does not apply.
PS1 Not assessed: no established pathogenic variant producing the same amino-acid change p.(Asp52Val) was available for comparison.
PS2 Not assessed: no de novo observation with parental testing was documented for this variant.
PS3 Not met: measured cumulative functional score 0.11 does not reach the <=-1.11 threshold for damaging phosphatase activity.
PS4 Not assessed: no affected-case series or case-control enrichment data were available.
PM1 Not met: Asp52 lies outside the PTEN catalytic domains (residues 90-94, 123-130, and 166-168).
PM4 Not met: p.(Asp52Val) is a single amino-acid substitution with no protein length change.
PM5 Not assessed: no pathogenic or likely pathogenic missense change at the same residue (Asp52) was available as a comparator.
PM6 Not assessed: no presumed de novo occurrence or phenotype/family-history data were documented.
PP1 Not assessed: no familial segregation data or informative transmissions were available.
PP5 Not assessed: no ClinVar expert-panel pathogenic or likely pathogenic assertion exists for this exact variant.
Benign
BA1 Not met: absent from gnomAD, below the >0.056% filtering allele-frequency threshold.
BS1 Not met: absent from gnomAD, with no allele frequency in the 0.00043%-0.056% BS1 range.
BS2 Not assessed: no homozygous observations in healthy or unaffected individuals were available.
BS4 Not assessed: no familial genotype-phenotype comparisons or non-segregation observations were documented.
BP2 Not assessed: no documented trans or cis observation with a pathogenic or likely pathogenic PTEN variant.
BP4 Not met: REVEL 0.95 is above the <0.5 threshold required for BP4.
BP5 Not assessed: no cases with an alternate molecular diagnosis were available.
BP6 Not assessed: no ClinVar expert-panel benign or likely benign assertion exists for this exact variant.
N/A · 5 PM3 · PP4 · BP1 · BP3 · BP7
Research & evidence
Population frequency
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 = 0.11). REVEL score = 0.95. BayesDel score = 0.53415.
SpliceAI ↗
Functional / OncoKB screenshot
Functional Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PTEN, a lipid and protein phosphatase, is one of the most frequently mutated genes in cancer.
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