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NM_000314.8:c.357dup
p.Ala120CysfsTer6 · PTEN
ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.2 · v3.2
0%
complete
Final classification
Likely Pathogenic
PVS1PM2
PTEN
c.357dup
p.Ala120CysfsTer6
frameshift · exon 5
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 loss-of-function variant is relevant to PTEN hamartoma tumor syndrome, an autosomal-dominant cancer predisposition disorder caused by impaired tumor-suppressor control of AKT/mTOR signaling.

Transcript
NM_000314.8
HGVS · transcript:coding
NM_000314.8:c.357dup
GRCh38
chr10:87933114 G>GT
GRCh37
chr10:89692871 G>GT
Likely Pathogenic: PVS1 (very strong) plus PM2 (supporting) satisfy the PTEN Expert Panel's Rule20.
Classification rationale
PVS1PM2 Likely Pathogenic
PTEN c.357dup frameshift · exon 5

PVS1 very strong: the early c.357 frameshift is 5' of the PTEN VCEP's c.1121 p.D375 NMD threshold. PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1.

PVS1 + PM2 → Likely Pathogenic
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 · 13 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: Full-strength PVS1 applies because the c.357 frameshift is 5' of the VCEP's c.1121 p.D375 NMD threshold in NM_000314.8.
Case normalization: NM_000314.8:c.357dup produces NP_000305.3:p.(Ala120CysfsTer6) / p.(A120Cfs*6), and the consequence class is frameshift.PTEN PVS1_DecisionTree_PTEN.pdf, page 1: the nonsense/frameshift path assigns PVS1 for a variant predicted to undergo NMD with disruption at or 5' to p.D375 (c.1121) when the exon is present in biologically relevant transcript NM_000314.8.Exact-notation search of PVS1_DecisionTree_PTEN.pdf.txt found no c.357dup, p.Ala120CysfsTer6, or p.A120Cfs*6 row; no variant-specific pre-assigned code was therefore available in that file.
cspec ↗vcep_pvs1_decisiontree_pten ↗
PM2 supporting Pathogenic
Met at Supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the PTEN VCEP requirement for frequency below 0.00001 (0.001%).
ClinGen PTEN VCEP Version 3.2, PM2 rule: databases 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 all-comers query: variant absent, consistent with allele frequency 0 and therefore below 0.00001 (0.001%).gnomAD v4.1 all-comers query: variant absent, consistent with allele frequency 0 and therefore below 0.00001 (0.001%).
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
Assessed · not applied · 4 not met · 9 not assessed
Pathogenic
PS2 Not assessed: no proband-level de novo observation, parental testing, maternity/paternity confirmation, or family-history information is documented.
PS3 Not assessed: mmc2.xlsx has no c.357dup or p.A120Cfs*6 entry, so the VCEP's <= -1.11 phosphatase-score rule cannot be evaluated.
PS4 Not assessed: no case-control odds ratio, confidence interval, or phenotype-specificity score is available to compare with the PTEN PS4 thresholds.
PM1 Not met: the frameshift starts at codon 120, outside the VCEP catalytic-motif intervals 90-94, 123-130, and 166-168.
PM6 Not assessed: no presumed de novo observation, affected proband documentation, family-history assessment, or parental-confirmation data is available.
PP1 Not assessed: no affected relatives, segregation results, family structure, or countable meioses are documented for c.357dup.
Benign
BA1 Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the 0.00056 (0.056%) BA1 threshold.
BS1 Not met: the variant is absent from gnomAD v2.1 and v4.1, so its observed frequency is not within either 0.0000043–0.00056 BS1 interval.
BS2 Not met: no homozygous healthy or PHTS-unaffected individual is reported, whereas the VCEP requires one confirmed or two unconfirmed observations.
BS3 Not assessed: mmc2.xlsx has no exact frameshift entry, so the VCEP's >0 phosphatase-activity rule cannot establish benign functional evidence.
BS4 Not assessed: no affected relatives or family-level lack-of-segregation observation is documented for c.357dup.
BP2 Not assessed: no cis, trans, or phase data, and no qualifying pathogenic/likely pathogenic PTEN partner observation is documented.
BP5 Not assessed: no two qualifying cases with a highly penetrant alternate diagnosis and non-overlapping PTEN histories are documented.
N/A · 13 PS1 · PM3 · PM4 · PM5 · PP2 · PP3 · PP4 · PP5 · BP1 · BP3 · BP4 · BP6 · 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 has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 2687567)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
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 previously been reported in somatic cancers (COSMIC; COSV64302704, n = 1 times).
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 · 5 PMIDs not cited in assessment
11237521 ↗ PTEN: life as a tumor suppressor. ONCOKB
17218262 ↗ Essential role for nuclear PTEN in maintaining chromosomal integrity. ONCOKB
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
31829902 ↗ Molecular Biomarkers in Localized Prostate Cancer: ASCO Guideline. CLINVAR
35924163 ↗ Genetic Testing and Its Clinical Application in Prostate Cancer Management: Consensus Statements from the Hong Kong Urological Association and Hong Kong Society of Uro-Oncology. CLINVAR