Variant classification summary

NM_000314.8:c.1033del

PTEN · NP_000305.3:p.(Leu345CysfsTer7) · NM_000314.8

GRCh37: chr10:89725049 GC>G · GRCh38: chr10:87965292 GC>G

Gene: PTEN Transcript: NM_000314.8

Final call

Pathogenic

PVS1 very strong PM1 moderate PM2 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Leu345CysfsTer7)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PVS1 (very strong) reflects the exon 9 frameshift and premature stop before the VCEP p.D375 threshold.

2

Pathogenic: PM1 (moderate) places residue 345 within the PTEN C2 functional domain spanning residues 186-351.

3

Pathogenic: PM2 (supporting) reflects absence from gnomAD v2.1 and v4.1.

Final determination: Rule3 of the ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.2 is satisfied by one very strong, one moderate, and one supporting pathogenic criterion.

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 at very strong strength: exon 9 frameshift p.Leu345CysfsTer7 creates a stop around p.352, 5' of the VCEP p.D375 NMD threshold.	cspec vcep_pvs1_decisiontree_pten pvs1_variant_assessment
PS1	N/A	Not applicable: c.1033del is a frameshift, not the missense or pathogenic-splicing comparator described by the VCEP PS1 rule.	cspec
PS2	Not assessed	Not assessed: no documented proband-level de novo observation with disease, no family history, and confirmed maternity and paternity is available.	cspec
PS3	Not assessed	Not assessed: the VCEP-assigned mmc2 functional table covers missense variants only, and no c.1033del, p.Leu345CysfsTer7, or p.L345Cfs*7 entry was found.	cspec vcep_mmc2 PMID:29706350
PS4	Not assessed	Not assessed: no PS4 case-control statistic or phenotype-specificity score is available to compare with the VCEP's score thresholds of 1-1.5, 2-3.5, 4-15.5, or ≥16.	cspec
PM1	Met	Met at moderate strength: residue 345 lies within the PTEN C2 functional domain spanning residues 186–351.	cspec PMID:11237521
PM2	Met	Met, supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the VCEP PM2 requirement of <0.00001 (0.001%) allele frequency.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN VCEP explicitly states that PM3 is not applicable to PTEN.	cspec
PM4	N/A	Not applicable: c.1033del is a frameshift with premature termination, whereas the PTEN VCEP PM4 rule covers only in-frame indels or stop-loss extensions.	cspec
PM5	N/A	Not applicable: the variant is a frameshift, whereas the VCEP PM5 rule requires a missense change at the same amino-acid residue.	cspec
PM6	Not assessed	Not assessed: no assumed de novo observation with disease and no family history, or count of proven versus assumed observations, is documented.	cspec
PP1	Not assessed	Not assessed: no affected-relative co-segregation data or informative meiosis count is documented for comparison with the VCEP's 3–4, 5–6, or ≥7 thresholds.	cspec
PP2	N/A	Not applicable: c.1033del is a frameshift, not the missense variant required by the VCEP PP2 rule.	cspec
PP3	N/A	Not applicable: c.1033del is a coding frameshift, whereas the PTEN PP3 rule covers splicing variants or missense variants, not frameshifts.	cspec
PP4	N/A	Not applicable: the PTEN VCEP incorporates phenotype specificity into PS4 Use 2 rather than allowing independent PP4 application.	cspec
PP5	N/A	Not applicable: the PTEN VCEP explicitly states that PP5 is not for use under the ClinGen SVI VCEP Review Committee recommendation.	cspec
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the >0.00056 (0.056%) BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, not within either VCEP BS1 frequency range of 0.0000043–0.00056.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports no variant observations, so no homozygous healthy or PHTS-unaffected individual is documented for the BS2 requirement.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: the VCEP-assigned mmc2 functional table covers missense variants only, and no c.1033del, p.Leu345CysfsTer7, or p.L345Cfs*7 entry was found.	cspec vcep_mmc2 PMID:29706350
BS4	Not assessed	Not assessed: no documented affected family member carrying the disease phenotype without the variant is available for one-family or two-family evaluation.	cspec
BP1	N/A	Not applicable: the PTEN VCEP explicitly designates BP1 as Not Applicable.	cspec
BP2	Not assessed	Not assessed: no documented trans observation or three qualifying cis/phase-unknown observations with different pathogenic PTEN variants.	cspec
BP3	N/A	Not applicable: the PTEN VCEP explicitly excludes BP3, and c.1033del is a premature-terminating frameshift rather than an in-frame repeat-region indel.	cspec
BP4	N/A	Not applicable: c.1033del is a truncating frameshift, outside the PTEN BP4 rule's splicing-variant and missense paths; SpliceAI 0.008 cannot negate the protein-truncating effect.	cspec
BP5	Not assessed	Not assessed: no two qualifying cases with a highly penetrant alternate disorder and non-overlapping personal or family history are documented for BP5.	cspec
BP6	N/A	Not applicable: the PTEN VCEP explicitly states that BP6 is not for use under the ClinGen SVI VCEP Review Committee recommendation.	cspec
BP7	N/A	Not applicable: c.1033del is an exon 9 coding frameshift, not a synonymous or intronic variant at or beyond +7/-21 as required by BP7.	cspec

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