Classification rationale

PVS1PM2 Likely Pathogenic

PTEN c.763_773del frameshift · exon 7

PVS1 very strong: the 11-bp deletion creates frameshift p.(Val255ProfsTer39) with its premature stop upstream of the PTEN NMD boundary p.D375 (c.1121), predicting loss of function via NMD. PM2 supporting: the variant is absent (AF=0) from gnomAD v2.1, v4.1, and gnomAD-Canada, below the PTEN Expert Panel's 0.001% overall allele-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 · 15 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): frameshift c.763_773del creates a stop at codon 293 (p.(Val255ProfsTer39)), 5' of PTEN's NMD cutoff p.D375 (c.1121), so NMD is predicted and PVS1 applies per the PTEN decision tree.

VariantValidator/Mutalyzer normalization: NM_000314.8:c.763_773del (11-nt deletion in exon 7) -> NP_000305.3:p.(Val255ProfsTer39); wild-type PTEN is 403 aa and the predicted mutant translation terminates at residue 293, so the premature stop is at protein position 293 (~c.877-879), well 5' of p.D375 (residue 375, c.1121).ClinGen PTEN EP cspec v3.2 (doc 135637575) lists PVS1 as applicable with rule 'Use PTEN PVS1 decision tree' and default strength Pathogenic Very Strong; framework_mode is vcep (VCEP spec governs over generic ACMG).PTEN EP specification text (PVS1 instructions): 'PVS1 applies to variants predicted to result in nonsense-mediated decay (NMD); the predicted NMD cutoff for PTEN occurs at c.1121 (p.D375).'

cspec ↗pvs1_generic_framework ↗gnomad_v2 ↗gnomad_v4 ↗

PM2 supporting Pathogenic

Met (supporting): the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (AF 0), meeting the PTEN EP PM2 threshold of <0.001% with no subpopulation alleles.

PTEN ClinGen Expert Panel (cspec v3.2) PM2 rule (Supporting only): 'Absent in population: 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 lookup (10-89717737-AGTAGAGTTCTT-A) returned the variant as absent (AF 0).gnomAD v4.1 lookup (chr10-87957980-AGTAGAGTTCTT-A) returned the variant as absent (AF 0).

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗cspec ↗

Assessed · not applied · 10 not met · 5 not assessed

Pathogenic

PS2 Not assessed: no confirmed de novo observation (maternity and paternity both confirmed, disease, no family history) exists, which PTEN VCEP PS2 requires.

PS3 Not assessed: no functional assay of this variant exists; the Mighell 2018 PTEN saturation assay scores only missense variants, not this c.763_773del frameshift.

PS4 Not met: no probands or case-control data exist for c.763_773del (ClinVar, gnomAD, literature all empty); phenotype specificity score 0 fails the >=1 supporting threshold.

PM1 Not met: PM1 residue 255 falls outside the PTEN VCEP catalytic motifs that define PM1 (90-94, 123-130, 166-168), and no VCEP domain table or hotspot includes it.

PM6 Not assessed: no presumed de novo occurrence (parents not tested, disease present, no family history) is documented, which PM6 requires.

PP1 Not assessed: no segregation observations exist; PP1 requires co-segregation in multiple affected family members with 3-4 meioses (supporting) and none are reported.

PP5 Not met: ClinVar has no entry for c.763_773del, so no exact-variant expert-panel Pathogenic/Likely pathogenic classification exists to support PP5.

Benign

BA1 Not met: gnomAD filtering AF is 0 (absent from gnomAD v2.1, v4.1, and gnomAD-Canada), far below the PTEN EP BA1 threshold of >0.00056.

BS1 Not met: the variant is absent from population databases (AF 0), below the PTEN EP BS1_Supporting floor of 0.0000043 filtering AF.

BS2 Not met: no homozygous observations exist; c.763_773del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (0 homozygotes).

BS3 Not met: no functional study shows preserved PTEN activity, and the truncating frameshift p.(Val255ProfsTer39) removes residues 255-403 of the 403-amino-acid protein.

BS4 Not assessed: no affected-family-member genotyping exists; BS4 requires demonstrated lack of segregation in affected members of one or more families, not merely absent data.

BP2 Not met: c.763_773del is absent from ClinVar and gnomAD with zero documented observations, so it is not observed in trans with a P/LP PTEN variant or in three cis/unknown-phase observations.

BP5 Not met: no case documents an alternate highly penetrant molecular cause with no PTEN phenotype overlap, and PTEN VCEP BP5 requires at least two such cases.

BP6 Not met: ClinVar has no entry for c.763_773del, so no exact-variant expert-panel Benign/Likely benign classification exists to support BP6.

N/A · 11 PS1 · PM3 · PM4 · PM5 · PP2 · PP3 · PP4 · BP1 · BP3 · BP4 · 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

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