Variant classification summary

NM_000314.8:c.449_456del

PTEN · NP_000305.3:p.(Glu150GlyfsTer27) · NM_000314.8

GRCh37: chr10:89692964 GAGGCCCTA>G · GRCh38: chr10:87933207 GAGGCCCTA>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.(Glu150GlyfsTer27)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PTEN c.449_456del (p.Glu150GlyfsTer27) 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, placing it below the PTEN Expert Panel PM2 population threshold of 0.001%.

3

This deletion is predicted to cause a frameshift with premature protein truncation, and under the PTEN-specific PVS1 decision tree its position 5' of c.1121 (p.D375) supports loss of function; SpliceAI does not predict an additional splice effect (maximum delta score 0.01).

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.449_456del, predicted to cause p.(Glu150GlyfsTer27). It occurs in exon 5 of the biologically relevant transcript and introduces a premature termination codon well 5' of the PTEN-specific c.1121 (p.D375) threshold, which meets the PTEN Expert Panel PVS1 decision tree for full-strength PVS1.	cspec vcep_pvs1_decisiontree_pten pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 applies to the same amino acid substitution as a previously established pathogenic variant or to certain equivalent splice effects. This variant is a frameshift deletion, so PS1 is not applicable.	cspec
PS2	Not assessed	No confirmed de novo observation with documented maternity and paternity testing was identified for this variant, so PS2 is not met from the available evidence.	cspec clinvar
PS3	Not assessed	No variant-specific functional assay or RNA study was identified for this frameshift deletion. The available PTEN functional assay resource in Mighell et al. is a missense assay and does not adjudicate this variant.	cspec vcep_mmc2 oncokb
PS4	Not assessed	No case series, prevalence comparison, or PTEN-specific proband scoring data were identified for this exact variant, so PS4 cannot be applied from the available evidence.	cspec clinvar gnomad_v2 gnomad_v4
PM1	Not met	This variant affects codon 150. The PTEN Expert Panel PM1 rule is defined for catalytic motif residues 90-94, 123-130, and 166-168, and no hotspot evidence was identified at residue 150, so PM1 is not met.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1. Its observed population frequency is therefore below the PTEN Expert Panel PM2 threshold of 0.001% and supports PM2 at the supporting level.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is designated not applicable in the PTEN Expert Panel specifications.	cspec
PM4	N/A	PM4 applies to in-frame insertions or deletions and stop-loss variants. This variant is a frameshift deletion, so PM4 is not applicable.	cspec pvs1_variant_assessment
PM5	N/A	PTEN uses classic same-residue missense PM5 logic. This variant is a frameshift deletion rather than a missense variant, so PM5 is not applicable.	cspec pm5_candidates
PM6	Not assessed	No assumed de novo observation without parental confirmation was identified for this variant, so PM6 cannot be applied from the available evidence.	cspec clinvar
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be applied.	cspec
PP2	N/A	PP2 is a missense criterion. This variant is a frameshift deletion, so PP2 is not applicable.	cspec
PP3	N/A	PTEN PP3 is specified for missense variants with REVEL >0.7 or for splicing variants with concordant splice prediction evidence. This variant is a frameshift deletion; REVEL and BayesDel were not applicable, and SpliceAI showed no significant splice effect with a maximum delta score of 0.01, so PP3 is not used.	cspec spliceai
PP4	N/A	PP4 is designated not applicable in the PTEN Expert Panel specifications because phenotype specificity is incorporated into PS4.	cspec
PP5	N/A	PP5 is designated not applicable in the PTEN Expert Panel specifications.	cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its population frequency is below the PTEN BA1 threshold of 0.056% and BA1 is not met.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its population frequency is below the PTEN BS1 thresholds of 0.00043% for supporting and 0.0043% for strong evidence. BS1 is not met.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No observations of this variant in healthy or PTEN hamartoma tumor syndrome-unaffected homozygous individuals were identified, so BS2 cannot be applied.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study showing no damaging effect was identified for this variant. The available PTEN missense phosphatase assay resource does not adjudicate this frameshift deletion.	cspec vcep_mmc2
BS4	Not assessed	No lack-of-segregation evidence was identified for this variant, so BS4 cannot be applied.	cspec
BP1	N/A	BP1 is designated not applicable in the PTEN Expert Panel specifications.	cspec
BP2	Not assessed	No phase-resolved co-occurrence with another pathogenic or likely pathogenic PTEN variant was identified, so BP2 cannot be applied.	cspec
BP3	N/A	BP3 is designated not applicable in the PTEN Expert Panel specifications.	cspec
BP4	N/A	PTEN BP4 is specified for synonymous or intronic variants with benign splice predictions or for missense variants with REVEL <0.5. This variant is a frameshift deletion; although SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, the BP4 rule is not applicable to this variant class.	cspec spliceai
BP5	Not assessed	No evidence was identified that this variant was found in an individual with a distinct alternate molecular diagnosis and non-overlapping clinical features, so BP5 cannot be applied.	cspec
BP6	N/A	BP6 is designated not applicable in the PTEN Expert Panel specifications.	cspec
BP7	N/A	BP7 applies to synonymous or qualifying deep intronic variants with no predicted splice impact. This variant is a coding frameshift deletion, so BP7 is not applicable.	cspec spliceai

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