Variant classification summary

NM_000314.6:c.95T>G

PTEN · NP_000305.3:p.(Ile32Ser) · NM_000314.6

GRCh37: chr10:89653797 T>G · GRCh38: chr10:87894040 T>G

Gene: PTEN Transcript: NM_000314.6

Final call

VUS

PS3 moderate PM2 supporting PP3 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.6

Protein

NP_000305.3:p.(Ile32Ser)

gnomAD AF

ClinVar

Likely pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 (Moderate): Mighell 2018 saturation mutagenesis measured a phosphatase activity score of -3.483, below the -1.11 pathogenic threshold.

2

PM2 (Supporting): variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (<0.001% allele frequency).

3

PP3 (Supporting): REVEL score 0.967 exceeds the 0.7 pathogenic-supporting threshold.

4

One Moderate and two Supporting criteria meet no CSPEC v3.2 combination rule, so the variant is classified as VUS.

Final determination: PTEN VCEP LP rules require Moderate>=3, or Moderate==2+Supporting>=2, or Moderate==1+Supporting>=4; adjudicated evidence (Moderate==1, Supporting==2) meets none, so classification is Uncertain Significance.

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: missense change produces no premature stop, frameshift, or canonical splice disruption, which PVS1 requires.	cspec vcep_pvs1_decisiontree_pten pvs1_variant_assessment pvs1_gene_context
PS1	Not assessed	Not assessed: insufficient evidence was available to determine whether this amino acid change matches a known pathogenic variant.
PS2	Not assessed	Not assessed: no confirmed de novo observation with proband phenotype, family history, or maternity/paternity documentation was available.	cspec clinvar
PS3	Met	Met (Moderate): Mighell 2018 saturation mutagenesis measured a phosphatase activity score of -3.483, well below the -1.11 pathogenic threshold.	vcep_mmc2 cspec
PS4	Not assessed	Not assessed: no case-control counts, phenotype-specificity scores, or enrichment statistics for this variant were available.	cspec clinvar
PM1	Not assessed	Not assessed: insufficient evidence was available to evaluate location in a PTEN functional domain or mutational hotspot.
PM2	Met	Met (Supporting): variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the <0.001% population-absence threshold.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM3	N/A	Not applicable: the PTEN Expert Panel specification designates PM3 as not applicable to this gene.	cspec
PM4	N/A	Not applicable: missense substitution alters one amino acid without changing protein length, so in-frame indel or stop-loss rules do not apply.	cspec pvs1_variant_assessment
PM5	Not assessed	Not assessed: insufficient evidence was available to assess other pathogenic missense changes at this same residue.
PM6	Not assessed	Not assessed: no assumed de novo observation with documented phenotype and family history was available.	cspec clinvar
PP1	Not assessed	Not assessed: no family segregation or meiosis data were available for this variant.	cspec
PP2	Not assessed	Not assessed: insufficient evidence was available to evaluate the gene's rate of benign missense variation.
PP3	Met	Met (Supporting): REVEL score 0.967 exceeds the VCEP's >0.7 pathogenic-supporting threshold for missense variants.	cspec revel
PP4	N/A	Not applicable: the PTEN Expert Panel specification designates PP4 as not applicable to this gene.	cspec
PP5	N/A	Not applicable: the PTEN specification excludes PP5, and no expert-panel submission exists for this exact variant.	cspec clinvar
BA1	Not met	Not met: variant is absent from gnomAD, with no allele frequency exceeding the >0.056% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS1	Not met	Not met: variant is absent from gnomAD, so no allele frequency falls in the BS1 range of 0.00043% to 0.056%.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS2	Not assessed	Not assessed: no homozygous observations of the variant in healthy individuals were documented.
BS3	Not met	Not met: measured phosphatase activity score -3.483 is far below zero, indicating damaging rather than benign function.	vcep_mmc2 cspec
BS4	Not assessed	Not assessed: no non-segregation data in affected family members were available.	cspec
BP1	Not assessed	Not assessed: insufficient evidence was available to evaluate whether only truncating variants cause disease in this gene.
BP2	Not assessed	Not assessed: no data on phase with a pathogenic PTEN variant or in-trans observations were available.	cspec
BP3	N/A	Not applicable: missense substitution involves no in-frame indel in a repetitive region.	cspec pvs1_variant_assessment
BP4	Not met	Not met: REVEL score 0.967 is far above the <0.5 benign-supporting threshold.	cspec revel
BP5	Not assessed	Not assessed: no alternate pathogenic molecular diagnosis or non-overlapping family history was available.	cspec
BP6	N/A	Not applicable: the PTEN specification excludes BP6, and no expert-panel benign assertion exists for this variant.	cspec clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous or intronic variants; this is a missense substitution.	cspec

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