Classification rationale

PVS1PM2 Likely Pathogenic

PTEN c.922_923insT frameshift · exon 8

PVS1 very strong: the c.922_923 frameshift lies before PTEN's NMD cutoff. 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 at very strong strength: the c.922_923 frameshift is 5' of PTEN's c.1121/p.D375 NMD cutoff in NM_000314.8.

Variant normalization: NM_000314.8:c.922_923insT produces NP_000305.3:p.(Arg308LeufsTer4) / p.(R308Lfs*4), and the consequence class is frameshift.ClinGen PTEN VCEP PVS1 instructions: PVS1 applies to variants predicted to result in NMD, with the predicted PTEN NMD cutoff at c.1121 (p.D375).PVS1_DecisionTree_PTEN.pdf, page 1: the frameshift/nonsense branch places variants predicted to undergo NMD with a stop codon or disruption at or 5' to p.D375 on the PVS1 branch; the biologically relevant transcript is NM_000314.8.

cspec ↗vcep_pvs1_decisiontree_pten ↗

PM2 supporting Pathogenic

Met at supporting strength: the variant was absent from gnomAD v2.1 and v4.1, satisfying the VCEP's <0.00001 (0.001%) population-frequency requirement.

ClinGen PTEN VCEP Version 3.2, PM2 Supporting rule: absent in population; databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population, with <0.00002 (0.002%) required in a subpopulation if multiple alleles are present.gnomAD v2.1 result for NM_000314.8:c.922_923insT: search_status=absent.gnomAD v4.1 result for NM_000314.8:c.922_923insT: search_status=absent.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 4 not met · 9 not assessed

Pathogenic

PS2 Not assessed: No documented proband de novo observation, confirmed maternity and paternity, disease status, or family-history evidence is available.

PS3 Not assessed: mmc2.xlsx contains no matching variant entry, and no qualifying functional assay result demonstrates a damaging effect for this frameshift.

PS4 Not assessed: no PTEN phenotype-specificity score, proband count, or qualifying case-control result is available.

PM1 Not met: residue 308 is outside the VCEP catalytic motifs 90–94, 123–130, and 166–168, with no documented hotspot evidence.

PM6 Not assessed: No assumed de novo observation with disease status, unconfirmed maternity and paternity, and no family history is documented.

PP1 Not assessed: No affected-family co-segregation data or meiosis count is documented, so the minimum 3-meiosis threshold cannot be evaluated.

Benign

BA1 Not met: the variant was absent from gnomAD v2.1 and v4.1, rather than exceeding the >0.00056 (0.056%) BA1 threshold.

BS1 Not met: the variant was absent from gnomAD v2.1 and v4.1, so its frequency did not reach the 0.0000043 (0.00043%) BS1-supporting lower bound.

BS2 Not met: gnomAD v2.1 and v4.1 reported no variant observation, so no homozygous healthy or PHTS-unaffected individual was identified.

BS3 Not assessed: mmc2.xlsx contains no matching variant entry, and no qualifying functional study shows no damaging effect on this frameshift’s protein function.

BS4 Not assessed: No family-level lack-of-segregation observation is documented, so the one-family and two-family thresholds cannot be evaluated.

BP2 Not assessed: no qualifying phase-resolved observation with a pathogenic or likely pathogenic PTEN variant is documented.

BP5 Not assessed: no two qualifying alternate-molecular-basis cases with highly penetrant disease 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

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 is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

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 · 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

Check your email

Reset your password

Enter an access code

Your allowance