The PTEN c.322C>G (p.Leu108Val) 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, gnomAD v4.1, and gnomAD-Canada v1.0, which supports rarity below the PTEN PM2 threshold of 0.001%.2 In the PTEN saturation mutagenesis phosphatase assay accepted by the PTEN Expert Panel, p.Leu108Val had a high-confidence cumulative fitness score of 1.160568514, which is above the BS3 threshold of >0 and well above the PS3_Moderate damaging threshold of ≤-1.11, supporting no damaging effect on protein function.3 Computational evidence is indeterminate overall: REVEL is 0.514, which is between the PTEN BP4 cutoff of <0.5 and PP3 cutoff of >0.7; BayesDel is 0.180271; and SpliceAI predicts no splice impact with a maximum delta score of 0.00.4
PTEN
Final classification
VUS
PTEN c.322C>G · p.Leu108Val
PTEN
The PTEN c.322C>G (p.Leu108Val) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.
Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting, PP2 supporting, BS3 supporting; no rule matched the adjudicated criteria.
Classification rationale
PM2PP2
BS3
VUS
PTEN c.322C>G
PM2 + PP2 + BS3
→
VUS
3
vcep_mmc2cspec ↗
4
revelbayesdelspliceai ↗cspec ↗
Gene diagram
· NM_000314.8 · variants mapped to exon structure
PTEN
NM_000314.8
Fetching transcript structure from UCSC…
Applied criteria · 3 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency
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 = 0.00). REVEL score = 0.514. BayesDel score = 0.180271.
Functional
Likely Oncogenic
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PTEN, a lipid and protein phosphatase, is one of the most frequently mutated genes in cancer.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 1 further PMID triaged but not cited — see Sources & References.
PMID PMID:29706350
Found
Structured finding pending for this record — see source link.
Applied to
→BS3 supports · met
Sources & reference links
9Sources
Triaged references · 1 PMID not cited in assessment
25527629 ↗
Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes.
ONCOKB