Variant classification summary

NM_000314.8:c.322C>G

PTEN · NP_000305.3:p.(Leu108Val) · NM_000314.8

GRCh37: chr10:89692838 C>G · GRCh38: chr10:87933081 C>G

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PM2 supporting PP2 supporting BS3 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Leu108Val)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PTEN c.322C>G (p.Leu108Val) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

2

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%.

3

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.

4

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.

Final determination: No criteria-combination rule matched the adjudicated criteria in the Richards et.al., 2015 - Combining rules v3.2.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This variant is a missense substitution, p.(Leu108Val), and does not fall within the PTEN null-variant categories used for PVS1.	pvs1_variant_assessment vcep_pvs1_decisiontree_pten cspec
PS1	Not assessed	No validated previously established pathogenic variant producing the same amino acid change was identified in the available evidence, so PS1 was not assessed.
PS2	Not assessed	No confirmed de novo observation with maternity and paternity established was identified for this variant.	clinvar
PS3	Not met	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.	vcep_mmc2 cspec
PS4	Not assessed	No affected-proband count, specificity score, or case-control enrichment data were identified for this variant.	clinvar
PM1	Not met	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.	cspec hotspots
PM2	Met	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 gnomad_v4 gnomad_canada cspec
PM3	N/A	PM3 is not applicable in the PTEN Expert Panel framework.	cspec
PM4	N/A	This variant does not cause a protein length change, in-frame insertion/deletion, or stop-loss event, so PM4 does not apply.	cspec
PM5	Not assessed	No validated pathogenic or likely pathogenic missense comparator at the same residue was established from the available evidence, so PM5 was not assessed.	pm5_candidates cspec
PM6	Not assessed	No assumed de novo observation without parental confirmation was identified for this variant.	clinvar
PP1	Not assessed	No segregation data were identified for this variant.	clinvar
PP2	Met	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.	cspec
PP3	Not met	Computational evidence does not meet the PTEN PP3 threshold for missense variants: REVEL is 0.514, which is below the required >0.7 threshold. SpliceAI predicts no splice impact with a maximum delta score of 0.00, and BayesDel is 0.180271 but does not overcome the PTEN-specific REVEL rule.	revel spliceai bayesdel cspec
PP4	N/A	PP4 is not applicable in the PTEN Expert Panel framework because phenotype specificity is incorporated into PS4.	cspec
PP5	N/A	PP5 is not applicable in the PTEN Expert Panel framework.	cspec
BA1	Not met	This variant is absent from population databases and does not meet the PTEN BA1 threshold of >0.056%.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS2	Not assessed	No healthy or PTEN-hamartoma-tumor-syndrome-unaffected homozygous observation was identified for this variant.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS3	Met	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.	vcep_mmc2 cspec
BS4	Not assessed	No lack-of-segregation data were identified for this variant.	clinvar
BP1	N/A	BP1 is not applicable in the PTEN Expert Panel framework.	cspec
BP2	Not assessed	No in trans, in cis, or phase-unknown observation with another pathogenic or likely pathogenic PTEN variant was identified for this variant.	clinvar
BP3	N/A	BP3 is not applicable in the PTEN Expert Panel framework.	cspec
BP4	Not met	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. SpliceAI predicts no splice impact with a maximum delta score of 0.00, but the PTEN missense BP4 rule is based on REVEL.	revel spliceai cspec
BP5	Not assessed	No alternate molecular explanation with non-overlapping phenotype information was identified for this variant.
BP6	N/A	BP6 is not applicable in the PTEN Expert Panel framework.	cspec
BP7	N/A	This variant is missense rather than synonymous or qualifying intronic, so BP7 does not apply.	cspec spliceai

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