Variant classification summary

NM_000314.8:c.387_388del

PTEN · NP_000305.3:p.(Arg130AsnfsTer49) · NM_000314.8

GRCh37: chr10:89692902 GAC>G · GRCh38: chr10:87933145 GAC>G

Gene: PTEN Transcript: NM_000314.8

Final call

Pathogenic

PVS1 very strong PM1 moderate PM2 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Arg130AsnfsTer49)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): 2-base-pair frameshift deletion (p.Arg130AsnfsTer49) predicted to trigger nonsense-mediated decay; loss of function is an established PTEN disease mechanism and the deletion removes most of the protein.

2

PM1 (Moderate): the deletion disrupts residue 130, the terminal residue of the PTEN catalytic motif (residues 123-130), a statistically significant mutational hotspot.

3

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

4

Overall classification: Pathogenic — PVS1 (Very Strong) + PM1 (Moderate) + PM2 (Supporting) satisfies Rule 3 of the ClinGen PTEN Expert Panel Specifications v3.2.

Final determination: Per the ClinGen PTEN Expert Panel Specifications v3.2 criteria-combination framework (mainRule Rule3): exactly one Very Strong criterion (PVS1) plus exactly one Moderate criterion (PM1) plus exactly one Supporting criterion (PM2) combines to 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	This 2-base-pair deletion shifts the reading frame (p.Arg130AsnfsTer49) and creates a premature stop codon at residue 178, well before the final exon-exon junction, so the message is predicted to be destroyed by nonsense-mediated decay. Loss of function is an established cause of PTEN-related disease, and the deletion removes most of the protein, including the C2 domain. Under the ClinGen PTEN expert panel rules, this meets PVS1 at Very Strong strength.	vcep_pvs1_decisiontree_pten cspec pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework gnomad_v2 gnomad_v4 gnomad_canada clinvar
PS1	N/A	PS1 compares a variant's amino-acid change with previously established pathogenic changes. This variant is a frameshift, which has no single alternate amino acid to compare, and it is not a splice-site variant (splice prediction is negligible), so PS1 does not apply.	cspec pm5_candidates spliceai
PS2	Not assessed	PS2 requires a confirmed de novo occurrence (new in the patient, with both parents tested). No proband-level clinical data, parental testing results, or family history were available for this variant, so this criterion could not be evaluated.	cspec clinvar
PS3	Not assessed	PS3 requires variant-specific functional assay evidence. No enzyme-activity, RNA, splicing, or cellular studies of this exact variant were available, and the PTEN saturation-mutagenesis assay covers missense variants only, so it does not apply to this frameshift. The variant's loss-of-function effect is instead captured by PVS1.	cspec vcep_mmc2 oncokb PMID:11237521 PMID:17218262
PS4	Not assessed	PS4 requires either a characteristic phenotype score in affected individuals or variant enrichment in cases versus controls. No proband phenotype data or case-control studies for this variant were available, so this criterion could not be evaluated.	cspec clinvar PMID:11237521 PMID:17218262
PM1	Met	The deletion disrupts codon 130, the terminal residue of the PTEN catalytic motif (residues 123-130), and the variant falls in a statistically significant mutational hotspot. Under the PTEN expert panel rules, which define PM1 positionally, this meets PM1 at Moderate strength.	cspec oncokb
PM2	Met	The variant is completely absent (zero alleles) from three large population datasets — gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada — consistent with a disease-causing variant under strong purifying selection. This meets PM2 at Supporting strength.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	PM3 applies to recessive disorders, where a variant is found paired with a pathogenic variant on the other copy of the gene. PTEN-related disease is autosomal dominant, and the PTEN expert panel explicitly excludes PM3, so it does not apply.	cspec
PM4	N/A	PM4 covers in-frame deletions or insertions that change protein length and stop-loss variants. This deletion removes 2 nucleotides (not a multiple of 3), making it a frameshift rather than an in-frame change, so PM4 does not apply; the frameshift effect is already scored under PVS1.	cspec
PM5	N/A	PM5 compares different missense changes at the same amino-acid position. This variant is a frameshift, not a missense change, so there is no alternate amino acid to compare and PM5 does not apply, even though other pathogenic missense changes at residue 130 are known.	cspec pm5_candidates
PM6	Not assessed	PM6 requires an assumed de novo occurrence (new in the patient without parental confirmation). No de novo observations of any kind were documented for this variant, so this criterion could not be evaluated.	cspec clinvar
PP1	Not assessed	PP1 requires evidence that the variant co-segregates with disease in affected family members. No affected relatives were tested and no segregation or pedigree data were available, so this criterion could not be evaluated.	cspec clinvar
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. This variant is a frameshift, not a missense change, so PP2 does not apply.	cspec
PP3	N/A	PP3's calibrated paths cover splice predictions for synonymous or intronic variants and REVEL scores for missense variants. This is an exonic frameshift, so neither path applies; splice prediction shows no impact on splicing, and applying PP3 would double-count the loss-of-function effect already scored under PVS1.	cspec spliceai
PP4	N/A	PP4 is not applicable because the PTEN expert panel has folded phenotype specificity into the PS4 rule and explicitly excludes PP4.	cspec
PP5	Not met	PP5 requires an expert-panel classification of this exact variant as pathogenic. The variant has no ClinVar entry at all, so no such classification exists and PP5 is not met.	clinvar oncokb cspec
BA1	Not met	BA1 requires a population allele frequency high enough to indicate a benign variant. This variant is absent from population databases (frequency of zero), far below the stand-alone benign threshold, so BA1 is not met.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	BS1 requires a low-but-present population allele frequency. The variant is absent (zero frequency), below even the lowest BS1 threshold, so BS1 is not met at any strength.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	BS2 requires the variant to be seen in the homozygous state in healthy individuals. The variant has no observations at all in population databases, so BS2 is not met.	gnomad_v2 gnomad_v4 gnomad_canada clinvar
BS3	Not assessed	BS3 requires functional studies showing the variant has no damaging effect. No such studies of this variant were available — the PTEN functional assays cover missense variants only — and all available evidence points to loss of function rather than benign behavior, so this criterion could not be evaluated.	cspec vcep_mmc2 spliceai oncokb PMID:11237521 PMID:17218262
BS4	Not assessed	BS4 requires family data showing the variant does not segregate with disease. No segregation or family studies of this variant were available, and absence of segregation data cannot be counted as evidence of lack of segregation, so this criterion could not be evaluated.	cspec clinvar
BP1	N/A	BP1 applies to genes where truncating variants are the only known disease mechanism. Missense variants are a common cause of PTEN disease, so the PTEN expert panel excludes BP1; the variant is also a frameshift, not a missense change.	cspec
BP2	Not met	BP2 requires observations of this variant paired with another pathogenic PTEN variant (in trans, or multiple in cis with phase unknown). No such observations exist — the variant is absent from ClinVar and population databases and is not reported in the available literature — so BP2 is not met.	cspec clinvar gnomad_v2 gnomad_v4 gnomad_canada PMID:11237521 PMID:17218262
BP3	N/A	BP3 covers in-frame insertions or deletions in repeat regions without known function. This is a frameshift deletion within the catalytic region, so BP3 does not apply.	cspec
BP4	N/A	BP4 requires multiple computational lines of evidence predicting no impact, defined for splice-site and missense variants. This is an exonic frameshift, so the calibrated paths do not apply, and a benign prediction would conflict with the loss-of-function evidence scored under PVS1.	cspec spliceai
BP5	Not assessed	BP5 requires documentation that the patient's disease has an alternate molecular cause. No case-level data describing such an alternate cause were available, so this criterion could not be evaluated.	cspec clinvar
BP6	Not met	BP6 requires an expert-panel classification of this exact variant as benign. The variant has no ClinVar entry at all, so no such classification exists and BP6 is not met.	clinvar cspec
BP7	N/A	BP7 applies to synonymous or intronic variants predicted not to affect splicing. This is a coding (exon 5) frameshift deletion, so BP7 does not apply.	cspec

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