0%
complete
Final classification
Likely Pathogenic
PVS1PM2
PTEN
c.763_773del
p.Val255ProfsTer39
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 Likely Pathogenic classification identifies c.763_773del as a loss-of-function PTEN allele: the frameshift is predicted to trigger nonsense-mediated decay, so no functional PTEN phosphatase is produced. Germline PTEN loss of function is the established cause of PTEN hamartoma tumor syndrome (Cowden syndrome), an inherited predisposition to breast and thyroid cancer, so this result aligns with the gene's known disease mechanism.

Transcript
NM_000314.8
HGVS · transcript:coding
NM_000314.8:c.763_773del
GRCh38
chr10:87957980 AGTAGAGTTCTT>A
GRCh37
chr10:89717737 AGTAGAGTTCTT>A
PVS1 (Very Strong) plus PM2 (Supporting) satisfies the ClinGen PTEN VCEP Rule20 combination (one Very Strong + one Supporting criterion), yielding Likely Pathogenic.
Classification rationale
PVS1PM2 Likely Pathogenic
PTEN c.763_773del frameshift · exon 7

PVS1 (Very Strong): out-of-frame 11-nucleotide deletion p.(Val255ProfsTer39) places a premature stop at residue 293, 5' of the p.D375 threshold, predicted to trigger nonsense-mediated decay. PM2 (Supporting): variant is absent (0 alleles) from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. PVS1 (Very Strong) plus PM2 (Supporting) satisfies the ClinGen PTEN VCEP Rule20 combination, yielding a final classification of Likely Pathogenic.

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 · 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 (Very Strong): the 11-nucleotide out-of-frame deletion p.(Val255ProfsTer39) places a premature stop at residue 293, 5' of the p.D375 NMD threshold, predicting nonsense-mediated decay.
ClinGen PTEN VCEP specification v3.2 (cspec) instructs that PVS1 be applied via the PTEN-specific PVS1 decision tree on biologically relevant transcript NM_000314.8, with PVS1 default strength Very Strong; generic ACMG PVS1 is superseded by this specification.Mutalyzer normalization of the case variant (prefetch) confirms NM_000314.8:c.763_773del = an 11-nucleotide deletion (11 is not a multiple of 3, hence out-of-frame) and predicts protein p.(Val255ProfsTer39): 293-residue predicted product versus 403-residue wild-type NP_000305.3, i.e. a frameshift starting at codon 255 with termination 39 residues into the shifted frame.The deleted nucleotides lie within coding exon 7 of the 9-exon canonical transcript NM_000314.8 (c.635-801 per transcript selector), not the terminal exon, and the premature termination codon (~p.293, exon 8) is located 5' to the PTEN decision-tree NMD/positional threshold p.D375 (c.1121).
cspec ↗
PM2 supporting Pathogenic
Met (Supporting): 0 alleles in gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, absent below the VCEP 0.001% population-frequency threshold.
ClinGen PTEN Expert Panel Specifications v3.2 (cspec) PM2: applicable at Supporting strength when 'Databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population. If multiple alleles are present within any subpopulation, allele frequency in that subpopulation must be <0.00002 (0.002%).'gnomAD v2.1 (GRCh37, exomes): variant 10-89717737-AGTAGAGTTCTT-A absent (search_status 'absent'); confirmed by screenshot.gnomAD v4.1 (GRCh38): variant chr10-87957980-AGTAGAGTTCTT-A absent (search_status 'absent'); confirmed by screenshot.
cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
Assessed · not applied · 5 not met · 8 not assessed
Pathogenic
PS2 Not assessed: no proband clinical data or parental testing were available to establish a proven de novo occurrence.
PS3 Not assessed: no variant-specific functional assay result was available; VCEP-calibrated PS3 thresholds cover only missense substitutions.
PS4 Not assessed: no proband phenotype data or case-control enrichment counts were available to score.
PM1 Not met: the deletion affects codon 255, outside the VCEP-defined catalytic motifs (residues 90-94, 123-130, 166-168), and no mutational hotspot was found.
PM6 Not assessed: no proband or parental data were available to determine an assumed de novo occurrence.
PP1 Not assessed: no pedigree or segregation data were available for this variant.
Benign
BA1 Not met: the variant is absent from gnomAD (0 alleles), far below BA1's required allele frequency above 0.056%.
BS1 Not met: absent from gnomAD (AF 0), below the BS1-supporting minimum allele frequency of 0.0000043.
BS2 Not met: zero alleles in population databases, so no homozygous observation in a healthy individual exists.
BS3 Not assessed: no functional assay evidence showing preserved function was available for this variant.
BS4 Not assessed: no family-testing data exist; absent segregation information cannot be counted as documented lack of segregation.
BP2 Not met: no observation of the variant in trans or in cis with a pathogenic PTEN variant exists (ClinVar has no entry).
BP5 Not assessed: no proband data on an alternate molecular diagnosis or non-overlapping family history were available.
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 is absent from ClinVar.
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 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