Classification rationale

PVS1PM2 Likely Pathogenic

PTEN c.521del frameshift · exon 6

PVS1 very strong: the frameshift is 5′ of PTEN p.D375/c.1121 and meets the Expert Panel's nonsense-mediated-decay rule. PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1, below the PTEN population-frequency threshold.

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: NM_000314.8:c.521del causes p.(Tyr174LeufsTer9), a frameshift 5′ of p.D375/c.1121, meeting the PTEN VCEP NMD branch.

The PTEN Expert Panel framework identifies NM_000314.8 as the preferred biologically relevant transcript and directs use of the PTEN PVS1 decision tree.The PTEN PVS1 decision tree assigns PVS1 when a nonsense or frameshift disruption at or 5′ to p.D375/c.1121 is predicted to undergo NMD in the biologically relevant transcript.The case variant is NM_000314.8:c.521del, a frameshift encoding NP_000305.3:p.(Tyr174LeufsTer9), which is upstream of c.1121 and therefore falls within the decision-tree full-strength branch.

cspec ↗

PM2 supporting Pathogenic

Met, supporting: the variant is absent (observed allele frequency 0) in gnomAD v2.1 and v4.1, below the PTEN PM2 threshold of 0.00001.

PTEN VCEP v3.2 specifies PM2 supporting for allele frequency <0.00001 (0.001%) in gnomAD or another large sequenced population; if multiple alleles are present in a subpopulation, that subpopulation frequency must be <0.00002 (0.002%).gnomAD v2.1 reports the variant as absent, corresponding to observed allele frequency 0 in that dataset.gnomAD v4.1 reports the variant as absent, corresponding to observed allele frequency 0 in that dataset.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 2 not met · 11 not assessed

Pathogenic

PS2 Not assessed: no proband diagnosis, parental testing, maternity/paternity confirmation, or family-history data are documented.

PS3 Not assessed: the PTEN VCEP assay table is restricted to missense variants, and no c.521del or p.Tyr174LeufsTer9 entry was found.

PS4 Not assessed: no case-control enrichment, confidence interval, or variant-specific phenotype score is available for applying the PTEN PS4 thresholds.

PM1 Not assessed: PTEN Y174 is reported as a hotspot, but the partial hotspot source lacks a valid source_registry key required to audit PM1 evidence.

PM6 Not assessed: no qualifying assumed de novo observation, proband disease documentation, family history, or count of independent observations is available.

PP1 Not assessed: no affected relatives, co-segregation observations, family structure, or meiosis count are documented.

Benign

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

BS1 Not met: the variant is absent from gnomAD, so its frequency does not fall within the PTEN BS1 interval of 0.0000043–0.00056.

BS2 Not assessed: no confirmed homozygous observation in a healthy or PHTS-unaffected individual is available for this absent variant.

BS3 Not assessed: no applicable benign functional assay was found, and the governing PTEN table contains no entry for this frameshift variant.

BS4 Not assessed: no non-segregating affected relatives, family segregation results, or number of families are documented.

BP2 Not assessed: no second pathogenic PTEN variant or cis/trans phase observation is documented for the required BP2 evidence.

BP5 Not assessed: no two qualifying cases with a highly penetrant alternate diagnosis and non-overlapping PTEN history 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 Hotspot

COSMIC

This variant lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant lies 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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