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

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): out-of-frame 11-nucleotide deletion p.(Val255ProfsTer39) places a premature stop at residue 293, 5' of the p.D375 threshold, predicted to trigger nonsense-mediated decay.

2

PM2 (Supporting): variant is absent (0 alleles) from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.

3

PVS1 (Very Strong) plus PM2 (Supporting) satisfies the ClinGen PTEN VCEP Rule20 combination, yielding a final classification of Likely Pathogenic.

Final determination: PTEN VCEP v3.2 Rule20: exactly 1 very strong pathogenic criterion (PVS1) plus exactly 1 supporting pathogenic criterion (PM2_Supporting) combines to 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): the 11-nucleotide out-of-frame deletion p.(Val255ProfsTer39) places a premature stop at residue 293, 5' of the p.D375 NMD threshold, predicting nonsense-mediated decay.	cspec vcep_pvs1_decisiontree_pten
PS1	N/A	Not applicable: this frameshift deletion is not a substitution, so no same-amino-acid comparison to a known pathogenic variant is possible.	cspec clinvar
PS2	Not assessed	Not assessed: no proband clinical data or parental testing were available to establish a proven de novo occurrence.	cspec clinvar
PS3	Not assessed	Not assessed: no variant-specific functional assay result was available; VCEP-calibrated PS3 thresholds cover only missense substitutions.	cspec vcep_mmc2 PMID:11237521 PMID:17218262
PS4	Not assessed	Not assessed: no proband phenotype data or case-control enrichment counts were available to score.	cspec clinvar
PM1	Not met	Not met: the deletion affects codon 255, outside the VCEP-defined catalytic motifs (residues 90-94, 123-130, 166-168), and no mutational hotspot was found.	cspec
PM2	Met	Met (Supporting): 0 alleles in gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, absent below the VCEP 0.001% population-frequency threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: the PTEN VCEP v3.2 designates PM3 not applicable because PTEN-related disease is autosomal dominant.	cspec
PM4	N/A	Not applicable: the deletion is out of frame (11 nucleotides), not an in-frame length change, so no protein-length alteration applies.	cspec
PM5	N/A	Not applicable: this is a frameshift deletion rather than a missense change, so PM5's missense and BLOSUM62 comparisons cannot apply.	cspec clinvar
PM6	Not assessed	Not assessed: no proband or parental data were available to determine an assumed de novo occurrence.	cspec clinvar
PP1	Not assessed	Not assessed: no pedigree or segregation data were available for this variant.	cspec clinvar
PP2	N/A	Not applicable: PP2 addresses missense variants, and this variant is a frameshift deletion.	cspec
PP3	N/A	Not applicable: PP3 is limited to missense variants (REVEL >0.7) and splice-relevant synonymous/intronic variants; this is a coding frameshift.	cspec spliceai
PP4	N/A	Not applicable: the PTEN VCEP captures phenotype specificity in PS4, and no proband phenotype data were available.	cspec
PP5	N/A	Not applicable: the PTEN VCEP lists PP5 as not applicable, and no ClinVar expert-panel classification exists for this variant.	cspec clinvar
BA1	Not met	Not met: the variant is absent from gnomAD (0 alleles), far below BA1's required allele frequency above 0.056%.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: absent from gnomAD (AF 0), below the BS1-supporting minimum allele frequency of 0.0000043.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Not met: zero alleles in population databases, so no homozygous observation in a healthy individual exists.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay evidence showing preserved function was available for this variant.	cspec vcep_mmc2 spliceai PMID:11237521 PMID:17218262
BS4	Not assessed	Not assessed: no family-testing data exist; absent segregation information cannot be counted as documented lack of segregation.	cspec clinvar
BP1	N/A	Not applicable: the PTEN VCEP marks BP1 not applicable, and this truncating frameshift is the opposite of the missense BP1 targets.	cspec
BP2	Not met	Not met: no observation of the variant in trans or in cis with a pathogenic PTEN variant exists (ClinVar has no entry).	cspec clinvar
BP3	N/A	Not applicable: PTEN VCEP v3.2 declares BP3 not applicable; the deletion is also out of frame, not an in-frame repeat indel.	cspec
BP4	N/A	Not applicable: BP4 applies only to missense (REVEL <0.5) or synonymous/intronic variants; this frameshift is protein-truncating by mechanism.	cspec spliceai
BP5	Not assessed	Not assessed: no proband data on an alternate molecular diagnosis or non-overlapping family history were available.	cspec clinvar
BP6	N/A	Not applicable: the PTEN VCEP lists BP6 as not applicable, and no ClinVar expert-panel benign classification exists for this variant.	cspec clinvar
BP7	N/A	Not applicable: BP7 covers only synonymous or intronic variants; this variant is an exonic frameshift deletion.	cspec

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