Variant classification summary

NM_000314.8:c.888T>A

PTEN · NP_000305.3:p.(Cys296Ter) · NM_000314.8

GRCh37: chr10:89720737 T>A · GRCh38: chr10:87960980 T>A

Gene: PTEN Transcript: NM_000314.8

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Cys296Ter)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): nonsense p.Cys296Ter — stop codon at 296, 5' to p.D375, predicted to trigger nonsense-mediated decay.

2

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

3

Overall: Likely Pathogenic under ClinGen PTEN EP v3.2 Rule20 (1 Pathogenic Very Strong + 1 Pathogenic Supporting).

Final determination: ClinGen PTEN EP v3.2 combination Rule20: exactly 1 criterion at Pathogenic Very Strong (PVS1) plus exactly 1 criterion at Pathogenic Supporting (PM2_Supporting) yields Likely Pathogenic; the generic ACMG fallback combination (PVS1 + 1 supporting = Likely Pathogenic, ClinGen SVI PM2 addendum) is consistent.

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	Met	Met: nonsense p.Cys296Ter — stop codon 296 lies 5' of p.D375/c.1121, predicted to trigger nonsense-mediated decay, satisfying the PTEN PVS1 tree at very strong strength.	vcep_pvs1_decisiontree_pten cspec pvs1_gene_context pvs1_variant_assessment gnomad_v2 gnomad_v4 gnomad_canada spliceai
PS1	Not met	Not met: no alternate nucleotide change at codon 296 produces p.Cys296Ter, and none is previously established as pathogenic.	cspec pm5_candidates
PS2	Not assessed	Not assessed: no parental testing, de novo observation, or family-history data exist for c.888T>A; ClinVar submissions lack inheritance details.	cspec
PS3	Not met	Not met: no RNA, mini-gene, or functional assay of c.888T>A exists; the VCEP assay table covers missense variants only.	cspec vcep_mmc2 oncokb spliceai PMID:11237521 PMID:17218262
PS4	Not assessed	Not assessed: no proband phenotype scores or case-control study data exist for c.888T>A; ClinVar carries only submission-level condition labels.	clinvar cspec PMID:26492180 PMID:27324988
PM1	Not met	Not met: p.Cys296 lies outside the PTEN-defined catalytic motifs (residues 90-94, 123-130, 166-168).	cspec
PM2	Met	Met: allele frequency 0 — absent from gnomAD v2.1, v4.1, and gnomAD-Canada, below the <0.00001 threshold; supporting strength.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM3	N/A	Not applicable: PM3 is a recessive-disorder criterion, and the PTEN VCEP explicitly marks it not applicable (autosomal dominant inheritance).	cspec
PM4	Not met	Not met: the variant is a truncating nonsense change, not an in-frame indel or stop-loss extension, so PM4 does not apply to this consequence class.	cspec
PM5	N/A	Not applicable: PM5 requires a missense change, and c.888T>A is a nonsense (stop-gain) variant; its null consequence is captured by PVS1.	cspec pm5_candidates
PM6	Not assessed	Not assessed: no assumed or presumed de novo observation of c.888T>A is documented, and no family-history data are available.	cspec
PP1	Not assessed	Not assessed: zero documented meioses — no segregation study or pedigree involving c.888T>A exists in the available literature.	cspec
PP2	N/A	Not applicable: PP2 applies to missense variants, and c.888T>A is a nonsense (stop-gain) change.	cspec
PP3	N/A	Not applicable: PP3 covers synonymous/intronic splice candidates and missense (REVEL >0.7); c.888T>A is a stop-gain with SpliceAI max delta 0.00.	cspec spliceai bayesdel clinvar
PP4	N/A	Not applicable: the PTEN VCEP explicitly lists PP4 as not applicable; phenotype specificity is captured by PS4 scoring instead.	cspec
PP5	N/A	Not applicable: VCV000917617 has no expert-panel submissions (2 stars, three clinical labs), so the PP5 override does not fire.	clinvar cspec
BA1	Not met	Not met: allele frequency 0, far below the gnomAD BA1 threshold of 0.00056.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS1	Not met	Not met: allele frequency 0 is below the lowest BS1 supporting-tier threshold of 0.0000043.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS2	Not met	Not met: zero homozygous or heterozygous observations in any population cohort; no healthy or unaffected homozygote data.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS3	Not met	Not met: no functional evidence of normal protein function exists; the VCEP assay covers missense variants only.	cspec vcep_mmc2 oncokb spliceai PMID:11237521 PMID:17218262
BS4	Not assessed	Not assessed: no documented non-segregation observation for c.888T>A; absence of segregation data cannot establish lack of segregation.	cspec
BP1	N/A	Not applicable: the PTEN VCEP marks BP1 not applicable, and the variant is truncating, not missense, in any case.	cspec
BP2	Not assessed	Not assessed: no trans/cis phase data — no second PTEN variant, parental testing, or phase information is documented for c.888T>A.	cspec clinvar PMID:26492180 PMID:27324988
BP3	N/A	Not applicable: the PTEN VCEP marks BP3 not applicable, and the variant is a nonsense substitution, not an in-frame indel in a repeat region.	cspec
BP4	N/A	Not applicable: BP4 covers synonymous/intronic and missense variants; a stop-gain's impact is established by the premature stop itself.	cspec spliceai bayesdel clinvar
BP5	Not assessed	Not assessed: no carrier-level clinical data — no alternate molecular cause or phenotype-overlap history is documented for c.888T>A.	cspec clinvar PMID:26492180 PMID:27324988
BP6	N/A	Not applicable: no expert-panel benign classification exists for this variant; the ClinVar label is Pathogenic/Likely pathogenic from non-expert labs.	clinvar cspec
BP7	N/A	Not applicable: BP7 applies to synonymous/intronic variants, and c.888T>A is a coding nonsense (stop-gain) change.	cspec spliceai clinvar

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