Classification rationale

PVS1PM2 Likely Pathogenic

PTEN c.585_586del frameshift · exon 6

Likely Pathogenic evidence: PVS1 very strong supports loss of function from a premature stop at p.200, before the VCEP p.D375 threshold. Likely Pathogenic evidence: PM2 supporting is met because 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 frameshift creates a stop at p.200, well 5' of the VCEP p.D375 NMD threshold in NM_000314.8.

Case consequence facts: NM_000314.8:c.585_586del is a frameshift with NP_000305.3:p.(Phe195LeufsTer6) / p.(F195Lfs*6).ClinGen PTEN VCEP PVS1 decision tree: the stop/disruption is at or 5' to p.D375 (c.1121), and the biologically relevant transcript is NM_000314.8; this is the full-strength PVS1 path.PVS1_DecisionTree_PTEN.pdf.txt was searched under c.585_586del, p.Phe195LeufsTer6, and p.F195Lfs*6; no pre-assigned variant-specific row was present.

cspec ↗vcep_pvs1_decisiontree_pten ↗

PM2 supporting Pathogenic

Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the VCEP's <0.00001 (0.001%) PM2 population-frequency requirement.

ClinGen PTEN VCEP Version 3.2 PM2 instruction: criteria may be applied below 0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population; if multiple alleles are present within a subpopulation, that subpopulation frequency must be below 0.00002 (0.002%).gnomAD v2.1 all-comers: NM_000314.8:c.585_586del absent.gnomAD v4.1 all-comers: NM_000314.8:c.585_586del absent.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

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

Pathogenic

PS2 Not assessed: no documented de novo observation with confirmed maternity and paternity, disease, and absence of family history is available.

PS3 Not assessed: mmc2 Table S2 contains no matching frameshift entry, and no reviewed paper provides variant-specific functional evidence meeting a PS3 threshold.

PS4 Not assessed: no VCEP-qualified phenotype-specific proband score or case-control odds ratio, p-value, and confidence interval is available.

PM1 Not met: residue 195 is outside the VCEP catalytic motifs 90-94, 123-130, and 166-168, and no hotspot was reported.

PM6 Not assessed: no de novo observation, disease status, family-history assessment, or parental-confirmation data are documented for the required PM6 thresholds.

PP1 Not assessed: no affected family members or countable segregation meioses are documented for the VCEP minimum of 3 meioses.

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 frequency is not within either VCEP BS1 interval.

BS2 Not met: no homozygous observations are reported in gnomAD v2.1 or v4.1, while the VCEP requires one confirmed or two unconfirmed observations.

BS3 Not assessed: mmc2 Table S2 contains no matching frameshift entry, and no reviewed paper provides variant-specific functional evidence showing preserved protein function.

BS4 Not assessed: no affected-family non-segregation observation is documented for either the one-family or two-family VCEP BS4 threshold.

BP2 Not assessed: no phase or allelic observations establish trans with one pathogenic variant or three cis/unknown-phase observations with different PTEN variants.

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 = 0.02).

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

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