Variant classification summary

NM_000314.8:c.890_899del

PTEN · NP_000305.3:p.(Asp297AlafsTer7) · NM_000314.8

GRCh37: chr10:89720738 GATCAAGAAAT>G · GRCh38: chr10:87960981 GATCAAGAAAT>G

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.(Asp297AlafsTer7)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PTEN c.890_899del (p.(Asp297AlafsTer7), p.(D297Afs*7)) 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 Expert Panel PM2_Supporting threshold of 0.00001 (0.001%).

3

This deletion causes a frameshift with premature termination, and under the PTEN-specific PVS1 decision tree a stop/disruption at or 5' to p.D375 (c.1121) in NM_000314.8 supports PVS1.

4

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.02; however, computational missense or splice criteria are not the primary basis for interpreting this truncating deletion.

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 deletion in PTEN, NM_000314.8:c.890_899del, predicted to result in p.(Asp297AlafsTer7) / p.(D297Afs*7). Under the PTEN-specific PVS1 decision tree, truncating variants with the stop/disruption at or 5' to p.D375 (c.1121) in the biologically relevant transcript NM_000314.8 meet PVS1; this variant is upstream of that threshold and PTEN loss of function is an established disease mechanism.	cspec vcep_pvs1_decisiontree_pten pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 is not applicable because this variant is a frameshift deletion, not an alternate nucleotide change producing the same amino acid substitution or the same predicted splice effect as a previously established pathogenic variant.	cspec
PS2	Not assessed	No confirmed de novo occurrence with maternity and paternity established was identified for this variant, so PS2 is not assessed.	clinvar
PS3	Not assessed	No variant-specific functional study demonstrating a damaging effect was identified for this deletion. The PTEN saturation mutagenesis assay referenced by the PTEN Expert Panel applies to missense variants, not this frameshift deletion, and no RNA study showing abnormal splicing was identified.	cspec vcep_mmc2 spliceai
PS4	Not assessed	No affected-case series, specificity score, or case-control enrichment data were identified for this variant, so PS4 is not assessed.	clinvar
PM1	Not met	This variant affects residue 297, which is outside the PTEN Expert Panel catalytic motif residues 90-94, 123-130, and 166-168 defined for PM1. No statistically significant hotspot evidence was identified for this site.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1. The PTEN Expert Panel PM2 threshold is allele frequency below 0.00001 (0.001%), with subpopulation allowance below 0.00002 (0.002%) if multiple alleles are present; the observed frequency is therefore below threshold and supports PM2 at supporting strength.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the PTEN Expert Panel framework.	cspec
PM4	N/A	PM4 is not applicable because this variant is a frameshift deletion rather than an in-frame insertion/deletion or stop-loss variant.	cspec
PM5	N/A	PM5 is not applicable because the PTEN framework uses classic same-residue missense PM5 logic, and this variant is a frameshift deletion rather than a missense change.	cspec pm5_candidates
PM6	Not assessed	No presumed de novo occurrence was identified for this variant, so PM6 is not assessed.	clinvar
PP1	Not assessed	No segregation data were identified for this variant, so PP1 is not assessed.	clinvar
PP2	N/A	PP2 is not applicable because this variant is not a missense change.	cspec
PP3	N/A	PP3 is not applied because the PTEN computational rule is intended for missense variants with REVEL greater than 0.7 or splicing variants with concordant splice predictors, and this variant is a frameshift deletion. SpliceAI showed no significant splice impact with a maximum delta score of 0.02, but that does not substitute for the truncating consequence that already drives interpretation.	cspec spliceai
PP4	N/A	PP4 is not applicable in the PTEN Expert Panel framework because phenotype specificity is incorporated into PS4.	cspec
PP5	N/A	PP5 is not applicable in the PTEN Expert Panel framework.	cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, so it does not meet the PTEN BA1 stand-alone benign threshold of filtering allele frequency greater than 0.00056 (0.056%).	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, so it does not meet the PTEN BS1 thresholds of 0.0000043 to 0.000043 for supporting evidence or 0.000043 to 0.00056 for strong evidence.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No observations of this variant in a healthy or PTEN-hamartoma-tumor-syndrome-unaffected homozygous individual were identified, so BS2 is not assessed.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established study showing no damaging effect was identified for this deletion. The PTEN functional assay referenced by the Expert Panel is a missense assay, and no RNA study demonstrating normal splicing was identified.	cspec vcep_mmc2 spliceai
BS4	Not assessed	No lack-of-segregation data were identified for this variant, so BS4 is not assessed.	clinvar
BP1	N/A	BP1 is not applicable in the PTEN Expert Panel framework.	cspec
BP2	Not assessed	No phase data were identified showing this variant in trans with a pathogenic PTEN variant or in cis/phase-unknown with multiple pathogenic PTEN variants, so BP2 is not assessed.	clinvar
BP3	N/A	BP3 is not applicable in the PTEN Expert Panel framework.	cspec
BP4	N/A	BP4 is not applied because the PTEN computational benign rule is intended for missense variants with REVEL below 0.5 or synonymous/intronic splicing variants with concordant benign splice predictions. This variant is a frameshift deletion; SpliceAI showed a low maximum delta score of 0.02, but that does not convert a truncating variant into benign computational evidence.	cspec spliceai
BP5	Not assessed	No evidence was identified that this variant was found in a case with an alternate highly penetrant molecular explanation and no overlap with PTEN-related disease, so BP5 is not assessed.
BP6	N/A	BP6 is not applicable in the PTEN Expert Panel framework.	cspec
BP7	N/A	BP7 is not applicable because this variant is not a synonymous or qualifying deep intronic change.	cspec

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