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 applied · 16 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, which is below the PTEN PM2 threshold of 0.001% and supports rarity.
gnomAD v2.1 absentgnomAD v4.1 absentgnomAD-Canada absent
✓
PP2
supporting
Pathogenic
This is a missense variant in PTEN, a gene for which the PTEN Expert Panel retains PP2 for missense variation as a disease mechanism with a low rate of benign missense variation.
Variant is missensePTEN CSPEC includes PP2
✓
BS3
supporting
Benign
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 supports no damaging effect on protein function.
Table S2 variant L108V / Leu108ValCum_score 1.160568514High_conf true
Assessed · not applied
Pathogenic
PS1
No validated previously established pathogenic variant producing the same amino acid change was identified in the available evidence, so PS1 was not assessed.
PS2
No confirmed de novo observation with maternity and paternity established was identified for this variant.
PS3
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 damaging threshold for PS3_Moderate of ≤-1.11 and does not support a damaging functional effect.
PS4
No affected-proband count, specificity score, or case-control enrichment data were identified for this variant.
PM1
Residue Leu108 is outside the PTEN Expert Panel PM1 catalytic motif ranges 90-94, 123-130, and 166-168, and the available hotspot review did not provide a confirmed hotspot call at this residue.
PM5
No validated pathogenic or likely pathogenic missense comparator at the same residue was established from the available evidence, so PM5 was not assessed.
PM6
No assumed de novo observation without parental confirmation was identified for this variant.
PP1
No segregation data were identified for this variant.
PP3
Computational evidence does not meet the PTEN PP3 threshold for missense variants: REVEL is 0.514, which is below the required >0.7 threshold.
Benign
BA1
This variant is absent from population databases and does not meet the PTEN BA1 threshold of >0.056%.
BS1
This variant is absent from population databases and does not meet the PTEN BS1 thresholds of 0.00043%-0.0043% for supporting or 0.0043%-0.056% for strong evidence.
BS2
No healthy or PTEN-hamartoma-tumor-syndrome-unaffected homozygous observation was identified for this variant.
BS4
No lack-of-segregation data were identified for this variant.
BP2
No in trans, in cis, or phase-unknown observation with another pathogenic or likely pathogenic PTEN variant was identified for this variant.
BP4
Computational evidence does not meet the PTEN BP4 threshold for missense variants because REVEL is 0.514, which is above the benign cutoff of <0.5.
BP5
No alternate molecular explanation with non-overlapping phenotype information was identified for this variant.
N/A · 9
PVS1 · PM3 · PM4 · PP4 · PP5 · BP1 · BP3 · BP6 · BP7
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