Classification rationale

PVS1PM2 Likely Pathogenic

PTEN c.888T>A

PVS1 (Very Strong): nonsense p.Cys296Ter — stop codon at 296, 5' to p.D375, predicted to trigger nonsense-mediated decay. PM2 (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency 0). Overall: Likely Pathogenic under ClinGen PTEN EP v3.2 Rule20 (1 Pathogenic Very Strong + 1 Pathogenic Supporting).

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 · 15 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PVS1 very strong Pathogenic

Met: nonsense p.Cys296Ter — stop codon 296 lies 5' of p.D375/c.1121, predicted to trigger nonsense-mediated decay, satisfying the PTEN PVS1 tree at very strong strength.

PTEN VCEP PVS1 decision tree (vcep_pvs1_decisiontree_pten, index.txt): nonsense/frameshift with stop codon or disruption at or 5' to p.D375 (c.1121), exon present in biologically-relevant transcript NM_000314.8 and predicted to undergo NMD -> PVS1; stop codon 3' to p.D375 not predicted to undergo NMD -> PVS1_ModerateClinGen PTEN EP CSPEC v3.2 PVS1 rule (cspec): 'Use PTEN PVS1 decision tree'; defaultStrength Pathogenic Very Strongprefetch normalization (Mutalyzer): NM_000314.8:c.888T>A -> NP_000305.3:p.(Cys296Ter); predicted protein MTAII...ENGSL* (296 aa) vs wild-type 403 aa

cspec ↗gnomad_v2 ↗

✓

PM2 supporting Pathogenic

Met: allele frequency 0 — absent from gnomAD v2.1, v4.1, and gnomAD-Canada, below the <0.00001 threshold; supporting strength.

gnomAD v2.1 (exome, GRCh37) variant page for 10-89720737-T-A: search_status 'absent', found=false — evidence_sentence 'Absent from gnomAD v2.1.'; screenshot gnomad_v2.png captured (manifest ok=true).gnomAD v4.1 (exome, GRCh38) variant page for 10-87960980-T-A: search_status 'absent', found=false — evidence_sentence 'Absent from gnomAD v4.1.'; screenshot gnomad_v4.png captured (manifest ok=true).gnomAD-Canada v1.0 (HostSeq genomes) API for 10-87960980-T-A: search_status 'absent', found=false — evidence_sentence 'Absent from gnomAD-Canada v1.0.'

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗cspec ↗

Assessed · not applied

Pathogenic

PS1 Not met: no alternate nucleotide change at codon 296 produces p.Cys296Ter, and none is previously established as pathogenic.

PS2 Not assessed: no parental testing, de novo observation, or family-history data exist for c.888T>A; ClinVar submissions lack inheritance details.

PS3 Not met: no RNA, mini-gene, or functional assay of c.888T>A exists; the VCEP assay table covers missense variants only.

PS4 Not assessed: no proband phenotype scores or case-control study data exist for c.888T>A; ClinVar carries only submission-level condition labels.

PM1 Not met: p.Cys296 lies outside the PTEN-defined catalytic motifs (residues 90-94, 123-130, 166-168).

PM4 Not met: the variant is a truncating nonsense change, not an in-frame indel or stop-loss extension, so PM4 does not apply to this consequence class.

PM6 Not assessed: no assumed or presumed de novo observation of c.888T>A is documented, and no family-history data are available.

PP1 Not assessed: zero documented meioses — no segregation study or pedigree involving c.888T>A exists in the available literature.

Benign

BA1 Not met: allele frequency 0, far below the gnomAD BA1 threshold of 0.00056.

BS1 Not met: allele frequency 0 is below the lowest BS1 supporting-tier threshold of 0.0000043.

BS2 Not met: zero homozygous or heterozygous observations in any population cohort; no healthy or unaffected homozygote data.

BS3 Not met: no functional evidence of normal protein function exists; the VCEP assay covers missense variants only.

BS4 Not assessed: no documented non-segregation observation for c.888T>A; absence of segregation data cannot establish lack of segregation.

BP2 Not assessed: no trans/cis phase data — no second PTEN variant, parental testing, or phase information is documented for c.888T>A.

BP5 Not assessed: no carrier-level clinical data — no alternate molecular cause or phenotype-overlap history is documented for c.888T>A.

N/A · 11 PM3 · PM5 · PP2 · PP3 · PP4 · PP5 · BP1 · BP3 · BP4 · BP6 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

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

This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 917617)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.60222.

SpliceAI ↗

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

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 · 8 PMIDs not cited in assessment

11237521 ↗ PTEN: life as a tumor suppressor. ONCOKB

17218262 ↗ Essential role for nuclear PTEN in maintaining chromosomal integrity. ONCOKB

20301661 ↗ PTEN Hamartoma Tumor Syndrome. CLINVAR

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

26389210 ↗ Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version. CLINVAR

26389333 ↗ Genetics of Skin Cancer (PDQ®): Health Professional Version. CLINVAR

26492180 ↗ Molecular Analysis of Mixed Endometrial Carcinomas Shows Clonality in Most Cases. CLINVAR

27324988 ↗ A Pilot Study of Clinical Targeted Next Generation Sequencing for Prostate Cancer: Consequences for Treatment and Genetic Counseling. CLINVAR