Variant classification summary

NM_000314.6:c.674_675dupAT

PTEN · NP_000305.3:p.(Ser226IlefsTer31) · NM_000314.6

GRCh37: chr10:89717644 G>GAT · GRCh38: chr10:87957887 G>GAT

Gene: PTEN Transcript: NM_000314.6

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.6

Protein

NP_000305.3:p.(Ser226IlefsTer31)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): frameshift duplication creates a premature stop (p.Ser226IlefsTer31) upstream of the last exon-exon junction, predicted to trigger nonsense-mediated decay.

2

PM2 (Supporting): variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0.

3

PVS1 (Very Strong) + PM2 (Supporting) -> Likely Pathogenic per the PTEN VCEP combination rule.

Final determination: PVS1 (Very Strong, ==1) combined with a single Supporting-tier criterion (PM2_Supporting) satisfies the ClinGen PTEN Expert Panel v3.2 criteria-combination rule mapping to 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	Met (Very Strong): frameshift duplication creates a premature stop (p.Ser226IlefsTer31) upstream of p.D375 and the last exon-exon junction, predicting nonsense-mediated decay.	cspec vcep_pvs1_decisiontree_pten
PS1	N/A	Not applicable: this frameshift duplication produces no defined amino acid substitution, so the missense-equivalence PS1 criterion does not apply.	cspec
PS2	Not assessed	Not assessed: no case documents an affected proband with both parents tested negative and confirmed parentage.	cspec
PS3	Not assessed	Not assessed: no functional study of this frameshift variant exists; the VCEP's functional criteria cover only missense and splicing variants.
PS4	Not assessed	Not assessed: no case-control enrichment statistics or qualifying phenotype-specific probands are available for this variant.	cspec PMID:21194675
PM1	N/A	Not applicable: the frameshift starts at residue Ser226, outside the PTEN catalytic motifs (residues 90-94, 123-130, 166-168).	cspec
PM2	Met	Met (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the panel's population-absence requirement.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: PTEN hamartoma tumor syndrome follows autosomal dominant inheritance, so the recessive PM3 criterion does not apply.	cspec
PM4	N/A	Not applicable: this out-of-frame 2-bp duplication is not an in-frame insertion/deletion or stop-loss variant; its loss-of-function effect is captured by PVS1.	cspec
PM5	N/A	Not applicable: PM5 requires a missense change at a residue with a known pathogenic missense; this is a frameshift.	cspec pm5_candidates
PM6	Not assessed	Not assessed: no presumed de novo observation is documented for this variant.	cspec
PP1	Not assessed	Not assessed: no affected relatives or segregation data are documented.	cspec
PP2	N/A	Not applicable: PP2 is restricted to missense variants; this is a frameshift duplication.	cspec
PP3	N/A	Not applicable: PP3 applies only to synonymous, intronic, or missense variants; this frameshift falls outside all three pathways.	cspec spliceai
PP4	N/A	Not applicable: phenotype specificity is already incorporated into PS4 under the PTEN expert panel rules.	cspec
PP5	N/A	Not applicable: the ClinVar record has only a single one-star laboratory submission, insufficient for PP5.	cspec clinvar
BA1	Not met	Not met: absent from gnomAD v2.1 and v4.1, so the allele frequency does not exceed the BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: absent from gnomAD v2.1 and v4.1, so no allele frequency reaches the BS1 threshold.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no homozygous unaffected or PHTS-negative individual carrying this variant has been observed.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional study shows normal function for this variant; the panel's functional evidence covers only missense and splicing variants.
BS4	Not assessed	Not assessed: no affected relative lacking the variant is documented, so non-segregation evidence is unavailable.	cspec
BP1	N/A	Not applicable: BP1 addresses missense variants in genes where truncation causes disease; the panel marks it not applicable for PTEN.	cspec
BP2	Not assessed	Not assessed: no observation places this variant in trans with a pathogenic PTEN variant.	cspec
BP3	N/A	Not applicable: BP3 addresses in-frame indels in repetitive regions; this is a frameshift duplication, and the panel marks BP3 not applicable for PTEN.	cspec
BP4	N/A	Not applicable: BP4 is restricted to synonymous, intronic, or missense variants; this frameshift is outside its scope.	cspec spliceai
BP5	Not assessed	Not assessed: no reports link this variant to an alternate molecular diagnosis in two or more cases.	cspec
BP6	N/A	Not applicable: the ClinVar record is a single one-star Pathogenic submission, not a benign expert-panel assertion.	cspec clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous or deep intronic variants; this is a frameshift duplication.	cspec

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