Variant classification summary

NM_000314.8:c.538del

PTEN · NP_000305.3:p.(Tyr180ThrfsTer3) · NM_000314.8

GRCh37: chr10:89711919 CT>C · GRCh38: chr10:87952162 CT>C

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.(Tyr180ThrfsTer3)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): frameshift p.(Tyr180ThrfsTer3) introduces a premature stop at residue 182, upstream of the PTEN p.Asp375 threshold and predicted to trigger nonsense-mediated decay.

2

PM2 (Supporting): variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the PTEN <0.001% population rarity requirement.

3

Overall: Likely Pathogenic by PTEN VCEP Rule20, combining one Very Strong (PVS1) and one Supporting (PM2) pathogenic criterion.

Final determination: Under ClinGen PTEN Expert Panel v3.2 Rule20, exactly one Pathogenic.Very Strong criterion (PVS1) plus exactly one Pathogenic.Supporting criterion (PM2_Supporting) classifies the variant as Likely Pathogenic.

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 (Very Strong): frameshift p.(Tyr180ThrfsTer3) stops translation at residue 182, upstream of the PTEN p.Asp375 threshold, with nonsense-mediated decay predicted.	cspec vcep_pvs1_decisiontree_pten
PS1	N/A	Not applicable: this is a frameshift, not a missense substitution, so no same-amino-acid comparison to an established pathogenic variant applies.	cspec
PS2	Not assessed	Not assessed: no parental testing, maternity or paternity confirmation, or phenotype data documenting a de novo occurrence was available.	cspec
PS3	Not assessed	Not assessed: no functional assay result exists for this exact frameshift; available PTEN phosphatase data cover only missense variants.	cspec vcep_mmc2 PMID:11237521 PMID:17218262
PS4	Not assessed	Not assessed: no affected-case counts, phenotype-specificity scores, or case-control data for this variant were available.	cspec
PM1	Not met	Not met: residue Tyr180 lies outside the PTEN catalytic motifs (WPD 90-94, P-loop 123-130, TI-loop 166-168) and no mutational hotspot was found.	cspec PMID:11237521
PM2	Met	Met (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the PTEN <0.001% population frequency requirement.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: the PTEN framework excludes PM3 because PTEN hamartoma tumor syndrome is an autosomal dominant disorder.	cspec
PM4	Not met	Not met: this is a frameshift, not an in-frame insertion/deletion or stop-loss variant, so PM4 does not apply.	cspec
PM5	N/A	Not applicable: PM5 requires a missense change at a residue with an established pathogenic missense, and c.538del is a frameshift.	cspec
PM6	Not assessed	Not assessed: no case observations or parental testing data from which a presumed de novo occurrence could be assigned were available.	cspec
PP1	Not assessed	Not assessed: no affected relatives carrying the variant, pedigree, or segregation data were available to evaluate co-segregation.	cspec
PP2	N/A	Not applicable: PP2 is specified for missense variants, and this variant is a frameshift.	cspec
PP3	N/A	Not applicable: PP3 covers missense or splice-region variants only; this is an exonic frameshift.	cspec spliceai
PP4	N/A	Not applicable: phenotype specificity is already captured within PS4 under the PTEN specification.	cspec
PP5	Not met	Not met: no ClinVar record exists for this exact variant, so no expert-panel pathogenic assertion could support it.	clinvar
BA1	Not met	Not met: BA1 requires gnomAD frequency above 0.056%; the variant is absent from all queried gnomAD datasets.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: BS1 requires gnomAD frequency of 0.00043% to 0.056%; the variant is absent from gnomAD.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no observation of the variant in the homozygous state in healthy or unaffected individuals was available.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no benign functional assay result exists for this exact frameshift variant.	cspec vcep_mmc2 PMID:11237521 PMID:17218262
BS4	Not assessed	Not assessed: no family testing or pedigree data showing lack of segregation were available.	cspec
BP1	N/A	Not applicable: the PTEN Expert Panel explicitly designates BP1 as not applicable to PTEN.	cspec
BP2	Not assessed	Not assessed: no co-occurring PTEN variant, phase information, or parental testing data were available.	cspec
BP3	N/A	Not applicable: the PTEN Expert Panel designates BP3 as not applicable to this gene.	cspec
BP4	N/A	Not applicable: BP4 covers synonymous, intronic, or qualifying missense variants only; this is an exonic frameshift.	cspec spliceai
BP5	Not assessed	Not assessed: no observation of this variant alongside a qualifying alternate molecular diagnosis was available.	cspec
BP6	Not met	Not met: no ClinVar record exists for this exact variant, so no expert-panel benign assertion could support it.	clinvar
BP7	N/A	Not applicable: BP7 covers only synonymous or deep intronic variants; this is an exonic frameshift.	cspec

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.