Variant classification summary

NM_000314.8:c.46T>G

PTEN · NP_000305.3:p.(Tyr16Asp) · NM_000314.8

GRCh37: chr10:89624272 T>G · GRCh38: chr10:87864515 T>G

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.(Tyr16Asp)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 (Moderate): direct saturation-mutagenesis assay (Mighell 2018) shows severely impaired lipid phosphatase function (fitness score -2.205, below the -1.11 threshold).

2

PM2 (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency 0, below 0.001%).

3

PP2 (Supporting): PTEN has a low rate of benign missense variation, and missense variants are a common disease mechanism.

4

PP3 (Supporting): REVEL score 0.844 exceeds the 0.7 threshold.

5

Overall classification: VUS — one moderate plus three supporting pathogenic criteria match no combination rule in the PTEN expert panel framework, with no strong/very-strong or benign criterion met.

Final determination: No criteria-combination rule in the ClinGen PTEN Expert Panel Specifications v3.2 (cspec doc 135637575) matched the adjudicated criteria set (PS3 moderate + PM2/PP2/PP3 supporting; no very-strong, strong, or benign criteria met), so the framework default classifies the variant as Variant of 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: this is a missense substitution, and the PTEN expert panel applies PVS1 only to null variants (nonsense, frameshift, splice-site, deletions).	vcep_pvs1_decisiontree_pten cspec
PS1	Not met	Not met: no alternate single-nucleotide change at codon 16 (TAT) can produce p.Tyr16Asp, so the same-amino-acid condition cannot be satisfied.	cspec clinvar spliceai
PS2	Not assessed	Insufficient evidence: no documented de novo occurrence or parental-testing data was available.	cspec clinvar
PS3	Met	Met (Moderate): the Mighell 2018 saturation-mutagenesis assay directly measured this variant at fitness score -2.205, below the -1.11 threshold.	PMID:29706350 vcep_mmc2 cspec oncokb
PS4	Not assessed	Insufficient evidence: no case-control study or phenotype-specificity scores for this variant were available.	cspec clinvar gnomad_v2 gnomad_v4 gnomad_canada
PM1	Not met	Not met: residue 16 lies outside the PTEN catalytic motifs (WPD loop, P-loop, TI-loop) that define PM1.	cspec
PM2	Met	Met (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency 0), below the 0.001% threshold.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM3	N/A	Not applicable: PM3 applies to recessive disorders, and PTEN hamartoma tumor syndrome is autosomal dominant.	cspec
PM4	N/A	Not applicable: this missense substitution leaves protein length unchanged, so no in-frame indel or stop-loss rule applies.	cspec
PM5	Not assessed	Insufficient evidence: no pathogenic same-residue comparator at Tyr16 could be confirmed.	pm5_candidates clinvar PMID:29706350 PMID:28481359
PM6	Not assessed	Insufficient evidence: no proband with a presumed de novo occurrence was available.	cspec clinvar
PP1	Not assessed	Insufficient evidence: no family segregation data was available, so co-segregation could not be evaluated.	cspec clinvar
PP2	Met	Met (Supporting): PTEN has a low rate of benign missense variation, and missense variants are a common disease mechanism.	cspec PMID:29706350
PP3	Met	Met (Supporting): REVEL score 0.844 exceeds the 0.7 missense threshold.	revel spliceai cspec bayesdel
PP4	N/A	Not applicable: the PTEN expert panel routes phenotype-specificity evidence through PS4, not PP4.	cspec
PP5	N/A	Not applicable: no expert-panel classification exists for this variant; ClinVar submissions are laboratory-only.	cspec clinvar
BA1	Not met	Not met: absent from gnomAD (allele frequency 0), far below the 0.056% stand-alone threshold.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS1	Not met	Not met: absent from gnomAD (allele frequency 0), below even the lowest supporting-strength frequency band.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS2	Not met	Not met: no homozygous observations in unaffected individuals exist; the variant is absent from population databases.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS3	Not met	Not met: the same validated assay shows severely reduced phosphatase activity (fitness score -2.205), not the >0 score BS3 requires.	PMID:29706350 vcep_mmc2 cspec
BS4	Not assessed	Insufficient evidence: no documented lack of segregation in affected family members was available.	cspec clinvar
BP1	N/A	Not applicable: missense variants are a common disease mechanism in PTEN, so this truncation-based rule does not apply.	cspec
BP2	Not met	Not met: no trans or cis observations alongside a pathogenic PTEN variant were found.	clinvar gnomad_v2 gnomad_v4 gnomad_canada
BP3	N/A	Not applicable: this is a missense substitution, not an in-frame indel in a repetitive region.	cspec
BP4	Not met	Not met: REVEL score 0.844 is above the 0.5 threshold BP4 requires for missense variants.	revel spliceai cspec bayesdel
BP5	Not assessed	Insufficient evidence: no case with an alternate molecular basis for disease was reported.	cspec
BP6	N/A	Not applicable: no expert-panel benign classification exists for this variant.	cspec clinvar
BP7	N/A	Not applicable: BP7 covers synonymous or intronic variants only; this is a missense substitution.	cspec spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.