Variant classification summary

NM_000314.8:c.395G>T

PTEN · NP_000305.3:p.(Gly132Val) · NM_000314.8

GRCh37: chr10:89692911 G>T · GRCh38: chr10:87933154 G>T

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PS3 moderate PM2 supporting PP2 supporting PP3 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Gly132Val)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 (Moderate): humanized-yeast phosphatase assay shows markedly reduced activity (Cum_score -4.003 vs the <=-1.11 threshold).

2

PM2 (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0.

3

PP2 (Supporting): PTEN has a low rate of benign missense variation, and missense is an established disease mechanism.

4

PP3 (Supporting): REVEL score 0.989, well above the >0.7 threshold.

5

Overall: VUS - these criteria satisfy no PTEN VCEP combination rule for Pathogenic, Likely Pathogenic, or Benign.

Final determination:

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	Not applicable: PVS1 applies only to null variants (nonsense, frameshift, splice disruption, initiation codon loss), and this is a missense change.	cspec
PS1	Not met	Not met: no alternate nucleotide change producing the same p.Gly132Val amino acid with an established pathogenic classification was identified.	cspec PMID:16773562
PS2	Not assessed	Not assessed: de novo occurrence is reported in one proband, but confirmed parentage and absence of family history are not documented.	cspec PMID:16752378
PS3	Met	Met (moderate): humanized-yeast phosphatase assay shows markedly reduced activity (Cum_score -4.003 vs the <=-1.11 threshold).	cspec vcep_mmc2 PMID:29706350
PS4	Not assessed	Not assessed: no independent affected individuals or case-control enrichment data were available.	cspec PMID:16752378 PMID:16773562
PM1	Not met	Not met: residue 132 falls just outside the PTEN catalytic motifs (P-loop 123-130, WPD loop 90-94, TI-loop 166-168).	cspec
PM2	Met	Met (supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, below the 0.001% allele-frequency threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: the PTEN VCEP marks PM3 as not applicable under the autosomal dominant inheritance model.	cspec
PM4	N/A	Not applicable: this missense substitution causes no change in protein length, which PM4 requires.	cspec
PM5	Not met	Not met: same-residue comparators (G132D, G132A) lack an established pathogenic or likely pathogenic classification.	cspec PMID:29706350 pm5_candidates
PM6	Not assessed	Not assessed: only one assumed de novo observation, with absence of family history not documented.	cspec PMID:16752378
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or co-segregation data are reported.	cspec
PP2	Met	Met (supporting): PTEN has a low rate of benign missense variation, and missense variants are an established disease mechanism.	cspec PMID:12471211
PP3	Met	Met (supporting): REVEL score 0.989, well above the >0.7 threshold.	cspec revel
PP4	N/A	Not applicable: phenotype specificity is incorporated into PS4 under the PTEN VCEP specification.	cspec
PP5	N/A	Not applicable: no ClinVar expert-panel pathogenic or likely pathogenic assertion exists for this variant.	clinvar
BA1	Not met	Not met: absent from gnomAD, so no allele frequency exceeds the >0.056% BA1 threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: absent from gnomAD, so no allele frequency falls within the 0.0043%-0.056% BS1 range.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no confirmed homozygous observation in a healthy or unaffected individual was available.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not met	Not met: assay Cum_score -4.003 shows markedly reduced activity, the opposite of the wild-type-comparable activity BS3 requires.	cspec vcep_mmc2 PMID:29706350
BS4	Not assessed	Not assessed: no affected family members are reported, so lack of segregation cannot be evaluated.	cspec
BP1	N/A	Not applicable: the PTEN VCEP specification explicitly designates BP1 as not applicable.	cspec
BP2	Not met	Not met: no pathogenic PTEN variant observed in trans, nor qualifying cis/phase-unknown observations.	cspec PMID:16752378 PMID:16773562
BP3	N/A	Not applicable: the PTEN VCEP marks BP3 as not applicable, and this is a missense change, not an in-frame indel.	cspec
BP4	Not met	Not met: REVEL score 0.989 is far above the <0.5 benign-supporting threshold.	cspec revel
BP5	Not assessed	Not assessed: no cases with an alternate molecular diagnosis were identified.	cspec
BP6	N/A	Not applicable: no ClinVar expert-panel benign or likely benign assertion exists for this variant.	clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous or intronic variants, not missense changes.	cspec

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