LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated:
Case ID: consistency_base
Framework: ACMG/AMP 2015
Variant classification summary

NM_000314.8:c.763_773del

PTEN  · NP_000305.3:p.(Val255ProfsTer39)  · NM_000314.8
GRCh37: chr10:89717737 AGTAGAGTTCTT>A  ·  GRCh38: chr10:87957980 AGTAGAGTTCTT>A
Gene: PTEN Transcript: NM_000314.8
Final call
Likely Pathogenic
PVS1 very strong PM2 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
PTEN
Transcript
NM_000314.8
Protein
NP_000305.3:p.(Val255ProfsTer39)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PVS1 very strong: the 11-bp deletion creates frameshift p.(Val255ProfsTer39) with its premature stop upstream of the PTEN NMD boundary p.D375 (c.1121), predicting loss of function via NMD.
2
PM2 supporting: the variant is absent (AF=0) from gnomAD v2.1, v4.1, and gnomAD-Canada, below the PTEN Expert Panel's 0.001% overall allele-frequency threshold.
Final determination: Under the ClinGen PTEN Expert Panel v3.2 criteria-combination framework (cspec doc 135637575), exactly one Pathogenic.Very Strong criterion (PVS1) plus exactly one Pathogenic.Supporting criterion (PM2) satisfies Rule20, which infers Likely Pathogenic; no Pathogenic or Benign/Likely Benign rule is matched by the adjudicated criteria.
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 c.763_773del creates a stop at codon 293 (p.(Val255ProfsTer39)), 5' of PTEN's NMD cutoff p.D375 (c.1121), so NMD is predicted and PVS1 applies per the PTEN decision tree.
cspec vcep_pvs1_decisiontree_pten pvs1_generic_framework gnomad_v2 gnomad_v4
PS1 N/A Not applicable: PS1 requires a missense identical to an established pathogenic change, but c.763_773del is a frameshift, p.(Val255ProfsTer39), with no ClinVar comparator.
cspec clinvar
PS2 Not assessed Not assessed: no confirmed de novo observation (maternity and paternity both confirmed, disease, no family history) exists, which PTEN VCEP PS2 requires.
cspec
PS3 Not assessed Not assessed: no functional assay of this variant exists; the Mighell 2018 PTEN saturation assay scores only missense variants, not this c.763_773del frameshift.
cspec vcep_mmc2 clinvar oncokb PMID:11237521 PMID:17218262
PS4 Not met Not met: no probands or case-control data exist for c.763_773del (ClinVar, gnomAD, literature all empty); phenotype specificity score 0 fails the >=1 supporting threshold.
cspec clinvar gnomad_v2 gnomad_v4 PMID:11237521 PMID:17218262
PM1 Not met Not met: PM1 residue 255 falls outside the PTEN VCEP catalytic motifs that define PM1 (90-94, 123-130, 166-168), and no VCEP domain table or hotspot includes it.
cspec
PM2 Met Met (supporting): the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (AF 0), meeting the PTEN EP PM2 threshold of <0.001% with no subpopulation alleles.
gnomad_v2 gnomad_v4 gnomad_canada cspec
PM3 N/A Not applicable: the ClinGen PTEN VCEP v3.2 specification states PM3 is not applicable to PTEN, an autosomal dominant disorder.
cspec
PM4 N/A Not applicable: PM4 requires an in-frame deletion/insertion or stop-loss variant; c.763_773del is an 11-bp out-of-frame deletion (p.(Val255ProfsTer39)) whose consequence is already captured by PVS1.
cspec
PM5 N/A Not applicable: PM5 requires a missense substitution at a residue where a different missense is established pathogenic; p.(Val255ProfsTer39) is a frameshift with no such comparator.
cspec clinvar
PM6 Not assessed Not assessed: no presumed de novo occurrence (parents not tested, disease present, no family history) is documented, which PM6 requires.
cspec
PP1 Not assessed Not assessed: no segregation observations exist; PP1 requires co-segregation in multiple affected family members with 3-4 meioses (supporting) and none are reported.
cspec
PP2 N/A Not applicable: PP2 applies only to missense variants in genes with low benign missense variation; c.763_773del is a truncating frameshift.
cspec gnomad_v2 gnomad_v4
PP3 N/A Not applicable: PP3 is limited to missense (REVEL >0.7) and splice-impact variants, but c.763_773del is a frameshift deletion, p.(Val255ProfsTer39).
cspec
PP4 N/A Not applicable: the ClinGen PTEN VCEP v3.2 declares PP4 not applicable because phenotype specificity is captured by PS4 Use 2.
cspec
PP5 Not met Not met: ClinVar has no entry for c.763_773del, so no exact-variant expert-panel Pathogenic/Likely pathogenic classification exists to support PP5.
clinvar cspec
BA1 Not met Not met: gnomAD filtering AF is 0 (absent from gnomAD v2.1, v4.1, and gnomAD-Canada), far below the PTEN EP BA1 threshold of >0.00056.
gnomad_v2 gnomad_v4 gnomad_canada cspec
BS1 Not met Not met: the variant is absent from population databases (AF 0), below the PTEN EP BS1_Supporting floor of 0.0000043 filtering AF.
gnomad_v2 gnomad_v4 gnomad_canada cspec
BS2 Not met Not met: no homozygous observations exist; c.763_773del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (0 homozygotes).
gnomad_v2 gnomad_v4 gnomad_canada clinvar cspec
BS3 Not met Not met: no functional study shows preserved PTEN activity, and the truncating frameshift p.(Val255ProfsTer39) removes residues 255-403 of the 403-amino-acid protein.
cspec vcep_mmc2 clinvar oncokb PMID:11237521 PMID:17218262
BS4 Not assessed Not assessed: no affected-family-member genotyping exists; BS4 requires demonstrated lack of segregation in affected members of one or more families, not merely absent data.
cspec
BP1 N/A Not applicable: the PTEN VCEP v3.2 specification marks BP1 not applicable, and generic BP1 targets missense variants, unlike this truncating frameshift.
cspec
BP2 Not met Not met: c.763_773del is absent from ClinVar and gnomAD with zero documented observations, so it is not observed in trans with a P/LP PTEN variant or in three cis/unknown-phase observations.
cspec clinvar gnomad_v2 gnomad_v4 gnomad_canada
BP3 N/A Not applicable: the PTEN VCEP v3.2 spec declares BP3 inapplicable to PTEN, and this out-of-frame 11-bp deletion is not an in-frame repeat-region indel.
cspec
BP4 N/A Not applicable: BP4 is limited to missense (REVEL <0.5) and splice-impact variants, but c.763_773del is a frameshift deletion, p.(Val255ProfsTer39).
cspec
BP5 Not met Not met: no case documents an alternate highly penetrant molecular cause with no PTEN phenotype overlap, and PTEN VCEP BP5 requires at least two such cases.
cspec
BP6 Not met Not met: ClinVar has no entry for c.763_773del, so no exact-variant expert-panel Benign/Likely benign classification exists to support BP6.
clinvar cspec
BP7 N/A Not applicable: BP7 covers only synonymous or intronic variants at or beyond +7/-21; c.763_773del is a frameshift deletion, p.(Val255ProfsTer39).
cspec
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