NM_000314.8:c.923del is a frameshift deletion in PTEN exon 8 resulting in a premature termination codon at p.Arg308LeufsTer9, which lies 5' to the p.D375 threshold and is predicted to undergo NMD, meeting PVS1 under the PTEN VCEP decision tree.1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength under PTEN VCEP (allele frequency < 0.001%).2 Under the PTEN VCEP combination rules (Version 3.2), PVS1 alone with PM2_Supporting does not satisfy any pathogenic or likely pathogenic classification rule. The variant has not been reported in ClinVar, has no de novo observations, no co-segregation data, and no variant-specific functional data.3 This variant has been observed in 7 somatic cancer samples (COSMIC: COSV64291945), and OncoKB classifies it as Likely Oncogenic with a predicted loss-of-function effect, consistent with PTEN's tumor suppressor role. However, somatic observations do not directly contribute to germline ACMG/AMP classification under the PTEN VCEP.4
PTEN
Final classification
Likely Pathogenic
PTEN c.923del · p.Arg308LeufsTer9
PTEN
NM_000314.8:c.923del is a frameshift deletion in PTEN exon 8 resulting in a premature termination codon at p.Arg308LeufsTer9, which lies 5' to the p.D375 threshold and is predicted to undergo NMD, meeting PVS1 under the PTEN VCEP decision tree.
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.923del
PVS1 + PM2
→
Likely Pathogenic
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
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
NM_000314.8:c.923del is a frameshift deletion in exon 8 producing a premature termination codon at p.(Arg308LeufsTer9). The new stop codon at position 316 lies 5' to the p.D375 (c.1121) positional threshold and is predicted to undergo nonsense-mediated decay (NMD). Exon 8 is present in the biologically-relevant transcript NM_000314.8. Under the PTEN VCEP PVS1 decision tree, a frameshift variant with stop codon 5' to p.D375 predicted to undergo NMD in a biologically-relevant transcript is assigned PVS1.
Frameshift deletion in exon 8 of 9 exonsPremature termination codon at p.Arg308LeufsTer9 (position 316)5' to p.D375 threshold (position 375)
✓
PM2
supporting
Pathogenic
NM_000314.8:c.923del is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Under PTEN VCEP, PM2_Supporting is applied when allele frequency is < 0.00001 (0.001%) in gnomAD or another large sequenced population.
Absent from gnomAD v2.1 (exomes)Absent from gnomAD v4.1 (exomes)Absent from gnomAD-Canada v1.0 (HostSeq genomes)
Assessed · not applied
Pathogenic
PS2
No de novo observation reported in ClinVar, the literature, or any database.
PS3
PTEN VCEP specifies PS3_Moderate for phosphatase activity ≤ -1.11 per Mighell et al.
PS4
No probands with specificity scores available for this variant.
PM1
PTEN VCEP defines PM1 for residues in catalytic motifs: 90-94, 123-130, and 166-168 (NP_000305.3).
PM6
No assumed or confirmed de novo observations identified in ClinVar, the literature, or any database.
PP1
No co-segregation data available for this variant.
Benign
BA1
PTEN VCEP applies BA1 when gnomAD filtering allele frequency exceeds 0.00056 (0.056%).
BS1
PTEN VCEP applies BS1_Strong at AF 0.000043-0.00056 and BS1_Supporting at AF 0.0000043-0.000043.
BS2
PTEN VCEP applies BS2 when the variant is observed in the homozygous state in a healthy or PHTS-unaffected individual.
BS3
PTEN VCEP specifies BS3 for functional studies showing no damaging effect.
BS4
PTEN VCEP applies BS4 when there is a lack of segregation in affected family members.
BP2
PTEN VCEP applies BP2 when the variant is observed in trans with a pathogenic or likely pathogenic PTEN variant, or at least three observations in cis/unknown phase with different P/LP PTEN variants.
BP5
PTEN VCEP applies BP5 when the variant is found in a case with an alternate molecular basis for disease, requiring at least two such cases.
N/A · 12
PS1 · PM4 · PM5 · PP2 · PP3 · PP4 · PP5 · BP1 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
v4.1
This variant is absent from gnomAD v4.1.
v2.1
This variant is absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
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 = 0.02).
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 previously been reported in somatic cancers (COSMIC; COSV64291945, n = 7 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 2 PMIDs not cited in assessment