Variant classification summary

NM_000314.8:c.570_571delinsT

PTEN · NP_000305.3:p.(Val191TrpfsTer8) · NM_000314.8

GRCh37: chr10:89711952 AG>T · GRCh38: chr10:87952195 AG>T

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.(Val191TrpfsTer8)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PTEN c.570_571delinsT (p.Val191TrpfsTer8; p.V191Wfs*8) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN VCEP PM2_Supporting population threshold of 0.001%.

3

This frameshift is predicted to introduce a premature stop codon after 8 altered amino acids at codon 191, and the PTEN VCEP PVS1 decision tree supports PVS1 for truncating variants at or 5' to p.D375 in the biologically relevant transcript NM_000314.8.

4

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.06.

Final determination: Rule20 in the Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified 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	This variant is a frameshift, NM_000314.8:c.570_571delinsT, predicted to result in p.(Val191TrpfsTer8) [p.(V191Wfs*8)] with a premature stop codon well 5' to the PTEN VCEP p.D375 (c.1121) threshold. PTEN loss of function is an established disease mechanism, and the PTEN-specific PVS1 decision tree supports full-strength PVS1 for truncating variants in this region of the biologically relevant transcript.	cspec pvs1_gene_context pvs1_variant_assessment vcep_pvs1_decisiontree_pten
PS1	N/A	This criterion is not applicable because the variant is a frameshift rather than a missense change or a nucleotide change being evaluated against a known pathogenic splicing variant at the same position.	cspec pvs1_variant_assessment
PS2	Not assessed	No confirmed de novo observation with maternity and paternity confirmed was identified for this variant, so PS2 cannot be applied from the available evidence.	clinvar
PS3	Not assessed	No variant-specific functional assay showing a damaging effect was identified for this frameshift variant. The PTEN VCEP supplementary functional assay resource is directed to missense variants, and no RNA or other direct assay evidence was available for this variant.	cspec vcep_mmc2 spliceai
PS4	Not assessed	No affected proband count, specificity score, or case-control enrichment data were identified for this variant, so PS4 cannot be applied.	clinvar
PM1	Not met	This variant affects codon 191, which is outside the PTEN catalytic motif residues defined for PM1 (90-94, 123-130, and 166-168). Available evidence does not support location in a PTEN mutational hotspot or critical domain specified for PM1.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1. Under the PTEN VCEP specification, PM2_Supporting is met when the allele frequency is <0.001% and, if multiple alleles are present in any subpopulation, that subpopulation frequency is <0.002%; this variant is below those thresholds.	cspec gnomad_v2 gnomad_v4
PM3	N/A	This criterion is not applicable in the PTEN VCEP framework.	cspec
PM4	N/A	This criterion is not applicable because the variant is a frameshift rather than an in-frame insertion/deletion or stop-loss variant.	cspec pvs1_variant_assessment
PM5	N/A	This criterion is not applicable because the PTEN framework uses classic same-residue missense PM5 logic, and this variant is not missense.	cspec pm5_candidates
PM6	Not assessed	No assumed or confirmed de novo observation was identified for this variant, so PM6 cannot be applied from the available evidence.	clinvar
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be applied.	clinvar
PP2	N/A	This criterion is not applicable because the variant is a frameshift rather than a missense variant.	cspec pvs1_variant_assessment
PP3	N/A	This criterion is not applicable because the PTEN PP3 computational rule is intended for missense REVEL interpretation or concordant splicing prediction for splice-relevant variants. This frameshift variant has no REVEL or BayesDel score, and SpliceAI shows no significant splice impact (max delta score 0.06).	cspec spliceai
PP4	N/A	This criterion is not applicable in the PTEN VCEP framework because phenotype specificity is incorporated into PS4 specifications.	cspec
PP5	N/A	This criterion is not applicable in the PTEN VCEP framework.	cspec
BA1	Not met	This variant is absent from gnomAD and does not meet the PTEN BA1 population threshold of >0.056% allele frequency.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD and does not meet the PTEN BS1 thresholds of 0.00043%-0.0043% for supporting evidence or 0.0043%-0.056% for strong evidence.	cspec gnomad_v2 gnomad_v4
BS2	Not met	No homozygous observation in a healthy or PTEN hamartoma tumor syndrome-unaffected individual was identified, so BS2 is not met.	gnomad_v2 gnomad_v4
BS3	Not assessed	No variant-specific functional study showing no damaging effect was identified. The PTEN VCEP missense functional assay resource does not directly address this frameshift variant.	cspec vcep_mmc2
BS4	Not assessed	No nonsegregation data were identified for this variant, so BS4 cannot be applied.	clinvar
BP1	N/A	This criterion is not applicable in the PTEN VCEP framework.	cspec
BP2	Not assessed	No phase data were identified showing this variant in trans with a pathogenic PTEN variant or repeated cis/phase-unknown observations with different pathogenic PTEN variants, so BP2 cannot be applied.	clinvar
BP3	N/A	This criterion is not applicable in the PTEN VCEP framework.	cspec
BP4	N/A	This criterion is not applicable because the PTEN BP4 computational rule is intended for synonymous or intronic variants with benign splicing predictions or missense variants with REVEL <0.5. This variant is a frameshift, and while SpliceAI predicts no significant splice impact (max delta score 0.06), that does not establish BP4 for this variant type.	cspec spliceai
BP5	Not assessed	No alternate highly penetrant molecular explanation with non-overlapping clinical features was identified, so BP5 cannot be applied.	clinvar
BP6	N/A	This criterion is not applicable in the PTEN VCEP framework.	cspec
BP7	N/A	This criterion is not applicable because the variant is neither synonymous nor intronic at or beyond the BP7 distance thresholds.	cspec pvs1_variant_assessment

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