Variant classification summary

NM_000314.8:c.898dupA

PTEN · NP_000305.3:p.(Ile300AsnfsTer3) · NM_000314.8

GRCh37: chr10:89720744 G>GA · GRCh38: chr10:87960987 G>GA

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.(Ile300AsnfsTer3)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PTEN c.898dup (p.Ile300AsnfsTer3; p.I300Nfs*3) variant has not been observed in COSMIC and has not been reported in ClinVar; OncoKB classifies it as likely oncogenic with a likely loss-of-function effect.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN PM2_Supporting threshold of 0.001% and is consistent with rarity in the general population.

3

This frameshift introduces a premature stop codon upstream of the PTEN-specific p.D375 (c.1121) threshold in NM_000314.8, which is consistent with predicted nonsense-mediated decay and supports PVS1 at very strong strength under the PTEN-specific decision tree.

4

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, indicating that the primary predicted effect is protein truncation rather than altered splicing.

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 frameshift variant is predicted to create p.(Ile300AsnfsTer3) with a premature stop codon well 5' of the PTEN-specific p.D375 (c.1121) threshold in biologically relevant transcript NM_000314.8, which is consistent with loss of function through nonsense-mediated decay. Germline loss of function is an established disease mechanism for PTEN, so this evidence meets PVS1 at very strong strength.	cspec vcep_pvs1_decisiontree_pten pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No evidence was identified showing that this variant produces the same amino acid change as a previously established pathogenic PTEN variant or the same nucleotide change as a known pathogenic splicing variant.	clinvar cspec
PS2	Not assessed	No confirmed de novo observation in an affected individual was identified for this variant.	cspec
PS3	Not assessed	No well-established variant-specific functional study was identified for this frameshift variant. The PTEN saturation mutagenesis phosphatase assay cited by the PTEN framework is for missense variants and does not provide a directly applicable result for this change.	cspec vcep_mmc2
PS4	Not assessed	No proband count, phenotype specificity score, or case-control enrichment data were identified for this variant, so increased prevalence in affected individuals could not be established.	clinvar cspec
PM1	N/A	PM1 is defined in the PTEN specification for variants affecting catalytic motif residues 90-94, 123-130, or 166-168. This frameshift affects codon 300, outside those PTEN catalytic motifs.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1. An observed allele frequency of 0 is below the PTEN PM2_Supporting threshold of 0.001% and is consistent with rarity in the general population.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	PM3 is marked not applicable in the PTEN expert specification.	cspec
PM4	N/A	PM4 is intended for in-frame insertions or deletions and stop-loss variants. This variant is a frameshift truncating change, so PM4 does not apply.	cspec
PM5	N/A	PM5 applies to missense changes at a residue where a different pathogenic missense change has been observed. This variant is a frameshift, not a missense substitution.	cspec
PM6	Not assessed	No assumed de novo observation was identified for this variant.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so co-segregation with PTEN-related disease could not be evaluated.	cspec
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. This variant is a frameshift and therefore PP2 does not apply.	cspec
PP3	N/A	PP3 is specified for missense prediction or splicing prediction concordance. This variant is a non-canonical frameshift change, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, so PP3 is not the relevant evidence path for this variant.	cspec spliceai
PP4	N/A	PP4 is marked not applicable in the PTEN expert specification.	cspec
PP5	N/A	PP5 is marked not applicable in the PTEN expert specification.	cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1. An observed allele frequency of 0 is below the PTEN BA1 threshold of 0.056%, so BA1 is not met.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1. An observed allele frequency of 0 is below the PTEN BS1_Supporting lower threshold of 0.00043% and below the BS1_Strong threshold range of 0.0043% to 0.056%, so BS1 is not met.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No observation of this variant in healthy or PTEN hamartoma tumor syndrome-unaffected homozygous individuals was identified.	cspec
BS3	Not assessed	No well-established functional study showing no damaging effect was identified for this variant. The PTEN phosphatase activity framework cited for BS3 applies to missense variants and does not provide a directly applicable benign result for this frameshift change.	cspec vcep_mmc2
BS4	Not assessed	No lack-of-segregation data were identified for this variant in affected family members.	cspec
BP1	N/A	BP1 is marked not applicable in the PTEN expert specification.	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.	cspec
BP3	N/A	BP3 is marked not applicable in the PTEN expert specification.	cspec
BP4	N/A	BP4 is specified for missense prediction or concordant splice prediction showing no impact. This variant is a frameshift, and although SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, that does not offset the truncating consequence, so BP4 does not apply.	cspec spliceai
BP5	Not assessed	No alternate highly penetrant molecular diagnosis with non-overlapping clinical features was identified for this case, so BP5 could not be evaluated.	cspec
BP6	N/A	BP6 is marked not applicable in the PTEN expert specification.	cspec
BP7	N/A	BP7 applies to synonymous or appropriately distal intronic variants with no predicted splice impact. This variant is a coding frameshift change, so BP7 does not apply.	cspec spliceai

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