Classification rationale

BS1 Likely Benign

PTEN c.-307C>G

The PTEN c.-307C>G (NP_000305.3:p.?) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.¹ This variant is absent from gnomAD v2.1, but in gnomAD v4.1 it is present at an overall allele frequency of 5.31e-06 and reaches 1.23e-04 in the Ashkenazi Jewish population, which meets the PTEN BS1 strong frequency range and is above the PTEN PM2 subpopulation threshold.² SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00, and no PTEN-specific computational evidence supporting a deleterious effect was identified.³

BS1 → Likely Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 spliceai ↗cspec ↗

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 · 1 applied · 14 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 · 1

Strength Supporting Moderate Strong Very strong

BS1 strong review Benign

Population frequency meets the PTEN BS1 strong threshold. The highest observed gnomAD v4.1 subpopulation allele frequency is 1.23e-04 in Ashkenazi Jewish individuals, which falls within the PTEN BS1 strong range of 4.3e-05 to 5.6e-04.

gnomAD v4.1 highest subpopulation AF 0.000122745 (2/16294 Ashkenazi Jewish alleles).

gnomad_v4 ↗cspec ↗

Assessed · not applied · 5 not met · 9 not assessed

Pathogenic

PS2 No confirmed de novo occurrence was identified for this variant, so PS2 cannot be assessed from the available evidence.

PS3 No well-established functional study was identified showing that this exact upstream variant damages PTEN function or splicing.

PS4 No affected-proband series, enrichment data, or case-control evidence was identified for this exact variant, so PS4 is not established.

PM2 Population frequency does not meet the PTEN PM2_Supporting threshold.

PM6 No presumed de novo observation was identified for this variant, so PM6 cannot be applied.

PP1 No segregation data were identified for this variant, so PP1 cannot be assessed.

PP3 Available computational evidence does not support a deleterious splicing effect under the PTEN PP3 rule.

Benign

BA1 Population frequency does not reach the PTEN BA1 threshold.

BS2 Available population data do not support BS2 because no homozygous individuals were reported in gnomAD for this variant.

BS3 No functional study was identified showing that this exact upstream variant has no damaging effect on PTEN function or splicing, so BS3 cannot be applied.

BS4 No lack-of-segregation evidence was identified for this variant, so BS4 cannot be assessed.

BP2 No phase data were identified showing this variant in trans with a pathogenic PTEN variant or repeatedly in cis/phase unknown with different pathogenic PTEN variants, so BP2 cannot be assessed.

BP4 Available computational evidence does not satisfy the PTEN BP4 rule for a benign prediction.

BP5 No alternate highly penetrant molecular diagnosis with a non-overlapping phenotype was identified, so BP5 cannot be assessed.

N/A · 13 PVS1 · PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · PP4 · PP5 · BP1 · BP3 · BP6 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 5.30724e-06; MAF= 0.00053%, 3/565266 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000122745; MAF= 0.01227%, 2/16294 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00053% · 3 / 565,266
0 hom

Ashkenazi Jewish 2 / 16,294	0.012%
European (non-Finnish) 1 / 316,368	0.00032%

+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, African/African American)

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

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

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

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