NM_000314.8:c.802-29C>A is absent from gnomAD v4.1 (0/1,512,514 alleles) and gnomAD v2.1, satisfying PM2 at supporting strength per the PTEN VCEP threshold of <0.001% allele frequency.1 This intronic variant at position -29 from the exon 8 acceptor splice site is at or beyond the -21 threshold. SpliceAI predicts no splicing impact (max delta 0.01; DS_AG=0.0, DS_AL=0.01, DS_DG=0.01, DS_DL=0.0), satisfying BP7 at supporting strength per the PTEN VCEP.2 No pathogenic or benign criteria at moderate or higher strength are met. With one pathogenic supporting criterion (PM2_Supporting) and one benign supporting criterion (BP7), the variant is classified as a Variant of Uncertain Significance (VUS). The variant has not been reported in ClinVar, COSMIC, or the published literature. No functional studies, segregation data, de novo observations, or case-control data are available.3
PTEN
Final classification
VUS
PTEN c.802-29C>A · p.?
PTEN
NM_000314.8:c.802-29C>A is absent from gnomAD v4.1 (0/1,512,514 alleles) and gnomAD v2.1, satisfying PM2 at supporting strength per the PTEN VCEP threshold of <0.001% allele frequency.
ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.2 v3.2 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting, BP7 supporting benign; no rule matched the adjudicated criteria.
Classification rationale
PM2
BP7
VUS
PTEN c.802-29C>A
PM2 + BP7
→
VUS
Gene diagram
· NM_000314.8 · variants mapped to exon structure
PTEN
NM_000314.8
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 14 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and v4.1 (0/1,512,514 alleles across all populations). The PTEN VCEP specifies PM2 at supporting strength when allele frequency is <0.001% (0.00001). The observed AF of 0 satisfies this threshold.
Absent from gnomAD v2.1 (exomes)Absent from gnomAD v4.1: 0/1512
✓
BP7
supporting
Benign
This is an intronic variant at c.802-29, which is beyond the -21 position from the exon 8 splice acceptor. SpliceAI predicts no impact to the splice consensus sequence and no creation of a new splice site (max delta 0.01, with individual delta scores: DS_AG=0.0, DS_AL=0.01, DS_DG=0.01, DS_DL=0.0). The PTEN VCEP BP7 applies at supporting level for intronic variants at or beyond +7/-21 where splicing prediction algorithms predict no impact.
Intronic variant at c.802-29 (beyond -21 from exon 8 splice acceptor)SpliceAI max delta 0.01 (DS_AG=0.0DS_AL=0.01
Assessed · not applied
Pathogenic
PS2
No de novo observations have been reported for this variant.
PS3
No functional assay data is available for this intronic variant.
PS4
No proband data or case-control studies are available for this variant.
PM6
No de novo observations have been reported for this variant.
PP1
No co-segregation data is available for this variant.
PP3
PP3 per PTEN VCEP requires multiple lines of computational evidence supporting a deleterious effect.
Benign
BA1
The PTEN VCEP BA1 threshold is a filtering allele frequency >0.056% (0.00056) in gnomAD.
BS1
The PTEN VCEP BS1 threshold is an allele frequency from 0.0043% (strong) or 0.00043% (supporting) up to 0.056%.
BS2
The PTEN VCEP BS2 requires observation in the homozygous state in a healthy or PHTS-unaffected individual.
BS3
The PTEN VCEP BS3_Strong requires an RNA, mini-gene, or other splicing assay demonstrating no splicing impact for intronic variants.
BS4
No segregation data is available for this variant.
BP2
The PTEN VCEP BP2 requires observation in trans with a pathogenic or likely pathogenic PTEN variant, or at least three observations in cis/unknown phase with different pathogenic/likely pathogenic PTEN variants.
BP4
The PTEN VCEP BP4 requires concordance of SpliceAI and VarSeak in silico models predicting no splicing impact for intronic variants.
BP5
The PTEN VCEP BP5 requires the variant to be found in at least two cases with an alternate molecular basis for disease, where the other gene/disorder is highly penetrant and the patient's personal/family history shows no overlap with PTEN.
N/A · 9
PVS1 · PS1 · PM1 · PM5 · PP2 · PP4 · PP5 · BP1 · BP6
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1512514 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/59236 alleles, homozygotes = 0).
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 / 1,512,514
0 hom
0 hom
Not observed in any ancestry group.
+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
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.
Sources & reference links