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NM_000314.8:c.771C>A
p.Phe257Leu · PTEN
ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.2 · v3.2
0%
complete
Final classification
VUS
PS3PM2
PTEN
c.771C>A
p.Phe257Leu
missense · 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

This PTEN missense variant affects a tumor-suppressor gene whose phosphatase activity restrains AKT/mTOR signaling and whose germline loss of function causes autosomal-dominant Cowden syndrome.

Transcript
NM_000314.8
HGVS · transcript:coding
NM_000314.8:c.771C>A
GRCh38
chr10:87957989 C>A
GRCh37
chr10:89717746 C>A
VUS: PS3 (moderate) plus PM2 (supporting) do not satisfy a PTEN Expert Panel pathogenic or benign combination rule.
Classification rationale
PS3PM2 VUS
PTEN c.771C>A missense · exon 7

PS3 Moderate: high-confidence PTEN F257L functional score of -2.055963973 supports impaired phosphatase activity. PM2 Supporting: the variant is absent from gnomAD v2.1 and v4.1.

PS3 + PM2 → VUS
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 · 17 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
PS3 moderate Pathogenic
Met at Moderate: PTEN F257L has high-confidence Cum_score -2.055963973, below the VCEP PS3 threshold of ≤ -1.11.
mmc2.xlsx, Table S2, row F257L/Phe257Leu: missense; Cum_score=-2.055963973; High_conf=True; Pass SE Filter; Imputed_score=NA.The PTEN VCEP file index declares mmc2.xlsx as governing PS3 and specifies PS3_Moderate when Cum_score <= -1.11 for this saturation-mutagenesis phosphatase assay.The assay is a massively parallel PTEN phosphatase-activity functional screen with cumulative fitness scores and high-confidence filtering as described in the governing file index.
cspec ↗vcep_mmc2 ↗PMID:29706350 ↗
PM2 supporting Pathogenic
Met, Supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the PTEN PM2 threshold of less than 0.00001 (0.001%) allele frequency.
ClinGen PTEN Expert Panel specification v3.2 assigns PM2 at supporting strength when databases are present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population; if multiple alleles are present within any subpopulation, that subpopulation allele frequency must be <0.00002 (0.002%).GNOMAD_V2_1 reports NM_000314.8:c.771C>A as absent, with no allele count, allele frequency, or subpopulation observation.GNOMAD_V4_1 reports NM_000314.8:c.771C>A as absent, with no allele count, allele frequency, or subpopulation observation.
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
Assessed · not applied · 6 not met · 11 not assessed
Pathogenic
PS1 Not assessed: no verified previously established pathogenic p.Phe257Leu or qualifying pathogenic splicing comparator was available for c.771C>A.
PS2 Not assessed: no documented proband de novo observation, confirmed maternity and paternity, or absence of family history is available.
PS4 Not assessed: no VCEP-required case-control statistics or proband phenotype-specificity score is available for this variant.
PM1 Not met: p.Phe257 is outside all three VCEP catalytic intervals (90–94, 123–130, and 166–168), and no statistically significant hotspot was identified.
PM5 Not assessed: no qualifying pathogenic or likely pathogenic different missense variant at PTEN residue 257 was available for the required BLOSUM62 comparison.
PM6 Not assessed: no documented presumed de novo proband, disease status, family-history assessment, or independent observation count is available.
PP1 Not assessed: no affected relatives, segregation results, or meiosis count are documented for comparison with the 3-meiosis minimum.
PP2 Not assessed: the variant is missense, but VCEP-governed evidence establishing both required PTEN gene-level conditions is unavailable.
PP3 Not met: the VCEP missense PP3 pathway requires REVEL > 0.7, but this variant's REVEL score is 0.631.
Benign
BA1 Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the PTEN BA1 threshold of 0.00056 (0.056%).
BS1 Not met: no allele frequency was observed in gnomAD v2.1 or v4.1, below the PTEN BS1 Supporting lower bound of 0.0000043 (0.00043%).
BS2 Not assessed: gnomAD reports no variant observation and provides no qualifying healthy or PHTS-unaffected homozygous individual under the PTEN BS2 rule.
BS3 Not met: PTEN F257L has high-confidence Cum_score -2.055963973, not the VCEP BS3 requirement of phosphatase activity >0.
BS4 Not assessed: no affected relatives lacking the variant or family-level non-segregation analysis is documented.
BP2 Not assessed: no documented trans observation or three cis/phase-unknown observations with different pathogenic/likely pathogenic PTEN variants were available.
BP4 Not met: the VCEP missense BP4 pathway requires REVEL < 0.5, but this variant's REVEL score is 0.631.
BP5 Not assessed: no qualifying alternate molecular diagnosis, two cases, penetrance evidence, or non-overlapping history is documented.
N/A · 9 PVS1 · PM3 · PM4 · PP4 · PP5 · BP1 · BP3 · BP6 · 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
Not available in 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 has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 492340)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.631. BayesDel score = 0.214994.
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 previously been reported in somatic cancers (COSMIC; COSV64295347, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 2 further PMIDs triaged but not cited — see Sources & references.
Mighell et al. 2018
PMID 29706350 ↗
Searched
c.771C>Ap.Phe257Leup.F257LF257LPhe257Leu
Found
Mighell et al. report the PTEN saturation-mutagenesis functional dataset used by the VCEP. The governing supplementary Table S2 contains the exact F257L/Phe257Leu missense row with Cum_score -2.055963973 and High_conf True (Pass SE Filter).
Variant
✓ Names this variant
Applied to
→PS3 moderate
The exact high-confidence functional row has Cum_score -2.055963973, meeting the VCEP PS3 Moderate threshold.
F257L Phe257Leu L (Leu) TTC TTG missense -2.055963973 0.382480215 True Pass SE Filter NA NA NA 0.404176742 -1.421894108 NA NA 0.437400295 -2.164016807 0.788846771 0.211508193 0.543335042 -2.768361959 NA NA -2.055963973 0.382480215
Location Supplementary mmc2.xlsx, Table S2, row F257L/Phe257Leu  ·  Context PTEN saturation mutagenesis and massively parallel phosphatase-activity functional screening; Table S2 reports cumulative fitness score, standard error, high-confidence status, replicate measurements, and imputation fields.
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
25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR
25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR