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PTEN
Final classification
Likely Pathogenic
PVS1PM2
PTEN
c.674_675dup
p.Ser226IlefsTer31
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

This frameshift duplication is predicted to trigger nonsense-mediated decay, eliminating PTEN's restraint on the AKT/mTOR growth pathway. Loss of PTEN function is the established mechanism of Cowden syndrome, so this Likely Pathogenic classification places the variant squarely within the gene's inherited cancer-predisposition role, notably elevated breast and thyroid cancer risk.

Transcript
NM_000314.6
HGVS · transcript:coding
NM_000314.6:c.674_675dup
GRCh38
chr10:87957887 G>GAT
GRCh37
chr10:89717644 G>GAT
Basis PVS1 at Very Strong plus PM2 at Supporting maps to Likely Pathogenic under the PTEN VCEP combination rule. ▾
PVS1 at Very Strong plus PM2 at Supporting maps to Likely Pathogenic under the PTEN VCEP combination rule.
Classification rationale
PVS1PM2 Likely Pathogenic
PTEN c.674_675dup frameshift · exon 7

PVS1 (Very Strong): frameshift duplication creates a premature stop (p.Ser226IlefsTer31) upstream of the last exon-exon junction, predicted to trigger nonsense-mediated decay. PM2 (Supporting): variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. PVS1 (Very Strong) + PM2 (Supporting) -> Likely Pathogenic per the PTEN VCEP combination rule.

PVS1 + PM2 → Likely Pathogenic
Gene diagram · NM_000314.6 · variants mapped to exon structure
PTEN NM_000314.6
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 12 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 duplication creates a premature stop (p.Ser226IlefsTer31) upstream of p.D375 and the last exon-exon junction, predicting nonsense-mediated decay.
PTEN VCEP PVS1 decision tree (PVS1_DecisionTree_PTEN.pdf) markdown extract: 'Predicted to undergo NMD: Stop codon or disruption at or 5' to Exon is present in biologically-relevant transcript NM_000314.8 PVS1 p.D375 (c.1121)... Not predicted to undergo NMD: Stop codon 3' to p.D375 (c.1121) PVS1_Moderate'.Mutalyzer/VariantValidator normalization: NM_000314.6:c.674_675dup gives protein consequence NP_000305.3:p.(Ser226IlefsTer31); variant_exonic_positions places the variant in exon 7 of the 9-exon transcript (NC_000010.10/NC_000010.11 start_exon=end_exon=7).Predicted protein sequence from prefetch shows the frameshifted ORF terminates at predicted residue position 256 (position_last_predicted=256), which is 5' to the p.D375/c.1121 threshold defined by the PTEN VCEP.
cspec ↗
✓
PM2 supporting Pathogenic
Met (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the panel's population-absence requirement.
ClinGen PTEN Expert Panel Specifications version 3.2 apply PM2 at Supporting strength for absence from population databases, or allele frequency <0.00001 (0.001%) in gnomAD or another large sequenced population; where multiple alleles occur in a subpopulation, subpopulation allele frequency must be <0.00002 (0.002%).The normalized variant 10-89717644-G-GAT is absent from gnomAD v2.1; 10-87957887-G-GAT is absent from gnomAD v4.1 and gnomAD-Canada v1.0.
cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
Assessed · not applied · 2 not met · 10 not assessed
Pathogenic
PS2 Not assessed: no case documents an affected proband with both parents tested negative and confirmed parentage.
PS3 Not assessed: no functional study of this frameshift variant exists; the VCEP's functional criteria cover only missense and splicing variants.
PS4 Not assessed: no case-control enrichment statistics or qualifying phenotype-specific probands are available for this variant.
PM6 Not assessed: no presumed de novo observation is documented for this variant.
PP1 Not assessed: no affected relatives or segregation data are documented.
Benign
BA1 Not met: absent from gnomAD v2.1 and v4.1, so the allele frequency does not exceed the BA1 threshold.
BS1 Not met: absent from gnomAD v2.1 and v4.1, so no allele frequency reaches the BS1 threshold.
BS2 Not assessed: no homozygous unaffected or PHTS-negative individual carrying this variant has been observed.
BS3 Not assessed: no functional study shows normal function for this variant; the panel's functional evidence covers only missense and splicing variants.
BS4 Not assessed: no affected relative lacking the variant is documented, so non-segregation evidence is unavailable.
BP2 Not assessed: no observation places this variant in trans with a pathogenic PTEN variant.
BP5 Not assessed: no reports link this variant to an alternate molecular diagnosis in two or more cases.
N/A · 14 PS1 · PM1 · 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 Pathogenic (1 clinical laboratory). (ClinVarID = 1456603)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10).
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; COSV99058014, 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
9467011 ↗ Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. CLINVAR
21194675 ↗ A clinical scoring system for selection of patients for PTEN mutation testing is proposed on the basis of a prospective study of 3042 probands. CLINVAR
28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR