NM_000314.8:c.927_937delinsT (p.Asp310ArgfsTer4) is a frameshift variant in exon 8 of PTEN, resulting in a premature termination codon at position 313. Per the PTEN-specific PVS1 decision tree, the stop codon lies 5' to the p.D375 (c.1121) NMD threshold, and the variant is predicted to undergo nonsense-mediated decay in the biologically-relevant transcript NM_000314.8. PVS1 is applied at very strong strength.1 The variant is absent from all population databases, including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (0 alleles). Per the PTEN VCEP, PM2 is applied at supporting strength for variants absent from large sequenced populations.2 This variant has not been reported in ClinVar and is absent from the somatic COSMIC database. No proband observations, co-segregation data, de novo reports, or functional studies were identified for this specific variant.3 SpliceAI predicts no significant splicing impact (max delta score = 0.04), consistent with the variant's mechanism operating through protein truncation rather than aberrant splicing.4
PTEN
Final classification
Likely Pathogenic
PTEN c.927_937delinsT · p.Asp310ArgfsTer4
PTEN
NM_000314.8:c.927_937delinsT (p.Asp310ArgfsTer4) is a frameshift variant in exon 8 of PTEN, resulting in a premature termination codon at position 313. Per the PTEN-specific PVS1 decision tree, the stop codon lies 5' to the p.D375 (c.1121) NMD threshold, and the variant is predicted to undergo nonsense-mediated decay in the biologically-relevant transcript NM_000314.8. PVS1 is applied at very strong strength.
ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.2 v3.2 criteria-combination framework: matched Rule20 (1 Pathogenic.Very Strong + 1 Pathogenic.Supporting) with applied criteria: PVS1 very strong, PM2 supporting; maps to Likely Pathogenic.
Classification rationale
PVS1PM2
Likely Pathogenic
PTEN c.927_937delinsT
PVS1 + PM2
→
Likely Pathogenic
1
vcep_pvs1_decisiontree_ptenpvs1_gene_contextpvs1_variant_assessment
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
✓
PVS1
very strong
Pathogenic
NM_000314.8:c.927_937delinsT is a frameshift variant predicted to result in a premature termination codon at p.Asp310ArgfsTer4 (p.313). Per the PTEN-specific PVS1 decision tree using transcript NM_000314.8, the stop codon occurs at position 313, which is 5' to the p.D375 (c.1121) NMD threshold, and the variant is predicted to undergo nonsense-mediated decay. The exon is present in the biologically-relevant transcript NM_000314.8. PVS1 is assigned at very strong strength.
Frameshift variant creates premature stop at p.3135' to p.D375 (c.1121) NMD thresholdExon 8 is present in biologically-relevant transcript NM_000314.8
✓
PM2
supporting
Pathogenic
NM_000314.8:c.927_937delinsT is absent from all population databases including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Per the PTEN VCEP, PM2 is applied at supporting strength when a variant is absent or present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population.
Absent from gnomAD v2.1 (0 alleles)Absent from gnomAD v4.1 (0 alleles)Absent from gnomAD-Canada v1.0 (0 alleles)
Assessed · not applied
Pathogenic
PS2
No de novo observation (confirmed or assumed) has been identified for NM_000314.8:c.927_937delinsT in the available evidence.
PS3
No variant-specific functional data is available for NM_000314.8:c.927_937delinsT.
PS4
No proband count or phenotype specificity score data is available for NM_000314.8:c.927_937delinsT.
PM1
The PTEN VCEP defines PM1 for variants located in catalytic motifs: WPD loop (residues 90-94), P-loop (residues 123-130), and TI-loop (residues 166-168) of NP_000305.3.
PM6
No assumed or confirmed de novo observation has been identified for NM_000314.8:c.927_937delinsT.
PP1
No co-segregation data is available for NM_000314.8:c.927_937delinsT.
Benign
BA1
The PTEN VCEP defines BA1 for variants with gnomAD filtering allele frequency >0.00056 (0.056%).
BS1
The PTEN VCEP defines BS1 at strong strength for gnomAD filtering AF from 0.000043 to 0.00056, and at supporting strength for AF from 0.0000043 to 0.000043.
BS2
The PTEN VCEP defines BS2 for a variant observed in the homozygous state in a healthy or PHTS-unaffected individual.
BS3
No well-established in vitro or in vivo functional studies demonstrate a lack of damaging effect for NM_000314.8:c.927_937delinsT.
BS4
The PTEN VCEP requires lack of segregation in affected members of two or more families for BS4 at strong strength, or one family for supporting strength.
BP2
The PTEN VCEP defines BP2 for a variant observed in trans with a pathogenic or likely pathogenic PTEN variant, or at least three observations in cis/phase unknown with different P/LP PTEN variants.
BP4
The PTEN VCEP defines BP4 for synonymous or intronic variants where SpliceAI (0-0.2) and VarSeak predict no splicing impact, or for missense variants with REVEL <0.5.
BP5
The PTEN VCEP defines BP5 for a variant found in a case with an alternate molecular basis for disease, requiring at least two such cases with the alternate gene being highly penetrant and no phenotypic overlap with PTEN.
N/A · 11
PS1 · PM4 · PM5 · PP2 · PP3 · PP4 · PP5 · BP1 · BP3 · 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
0 hom
Not observed in any ancestry group.
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 = 0.04).
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.
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.
Sources & reference links
9Sources
Triaged references · 2 PMIDs not cited in assessment