Variant classification summary

NM_000314.8:c.197_203del

PTEN · NP_000305.3:p.(Lys66ThrfsTer31) · NM_000314.8

GRCh37: chr10:89685300 CAAGATAT>C · GRCh38: chr10:87925543 CAAGATAT>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.(Lys66ThrfsTer31)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): 7-bp frameshift deletion (p.Lys66ThrfsTer31) truncating 5' of the p.D375 threshold, predicted to trigger nonsense-mediated decay.

2

PM2 (Supporting): variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, below the 0.001% population-frequency threshold.

3

PVS1 + PM2 satisfies Rule 20 of the PTEN VCEP, producing a Likely Pathogenic classification.

Final determination: PTEN VCEP Rule20 (ClinGen PTEN Expert Panel Specifications v3.2, cspec_ruleset): 1 Pathogenic.Very Strong criterion (PVS1) AND 1 Pathogenic.Supporting criterion (PM2 supporting) -> 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): 7-bp frameshift deletion (p.Lys66ThrfsTer31) truncates the protein 5' of the p.D375 threshold, predicted to trigger nonsense-mediated decay.	cspec vcep_pvs1_decisiontree_pten
PS1	N/A	Not applicable: a frameshift deletion produces no discrete amino-acid change to compare against a pathogenic missense precedent.	cspec
PS2	Not assessed	Not assessed: no proband, de novo observation, or parental-testing results were available.	cspec
PS3	Not assessed	Not assessed: the VCEP functional assay covers only missense variants, and no variant-specific functional study was available.
PS4	Not assessed	Not assessed: no case-control counts, odds ratios, or phenotype-specificity data were available for this variant.	cspec clinvar
PM1	N/A	Not applicable: a frameshift at codon 66 lies outside the catalytic-motif hotspot residues 90-94, 123-130, and 166-168.	cspec
PM2	Met	Met (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada, below the 0.001% population-frequency threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: designated not applicable by the PTEN Expert Panel because PTEN hamartoma tumor syndrome is autosomal dominant.	cspec
PM4	N/A	Not applicable: the 7-bp deletion causes a frameshift, not an in-frame length change or stop-loss protein extension.	cspec
PM5	N/A	Not applicable: this is a frameshift deletion, not a missense change, so no BLOSUM62 comparison applies.	cspec
PM6	Not assessed	Not assessed: no documented de novo occurrence or parental-testing results were available.	cspec
PP1	Not assessed	Not assessed: no affected relatives or segregation results were reported.	cspec
PP2	N/A	Not applicable: PP2 applies only to missense variants; this is a frameshift deletion.	cspec
PP3	N/A	Not applicable: the VCEP computational pathway covers only missense (REVEL) and splicing variants, not frameshift deletions.	cspec
PP4	N/A	Not applicable: designated not applicable by the PTEN Expert Panel; phenotype specificity is covered under PS4.	cspec
PP5	Not assessed	Not assessed: no exact-variant ClinVar expert-panel classification was available.	clinvar
BA1	Not met	Not met: variant is absent from gnomAD, so the >0.056% BA1 frequency threshold is not reached.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: variant is absent from gnomAD, so neither the strong nor supporting BS1 frequency interval is reached.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no homozygous observations in healthy or unaffected individuals were available.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: the VCEP benign functional assay covers only missense variants, and no variant-specific study was available.
BS4	Not assessed	Not assessed: no family members lacking the variant were documented, so lack of segregation could not be established.	cspec
BP1	N/A	Not applicable: designated not applicable gene-wide by the PTEN VCEP; also a frameshift, not a missense change.	cspec
BP2	Not assessed	Not assessed: no cis, trans, or phase observations with pathogenic PTEN variants were available.	cspec
BP3	N/A	Not applicable: designated not applicable for PTEN by the VCEP specification.	cspec
BP4	N/A	Not applicable: BP4 applies only to missense (REVEL) and splicing variants; this is a frameshift deletion.	cspec
BP5	Not assessed	Not assessed: no cases with an alternate molecular basis or non-overlapping phenotype were available.	cspec
BP6	N/A	Not applicable: designated not applicable by the PTEN Expert Panel, and the variant is absent from ClinVar.	cspec clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous or intronic variants; this is a coding frameshift deletion.	cspec

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