Variant classification summary

NM_000314.8:c.1012_1016del

PTEN · NP_000305.3:p.(Ser338LysfsTer3) · NM_000314.8

GRCh37: chr10:89720860 TTCTCC>T · GRCh38: chr10:87961103 TTCTCC>T

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.(Ser338LysfsTer3)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PVS1 (very strong) reflects a truncating frameshift upstream of the PTEN VCEP NMD threshold.

2

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

Final determination: Under Rule20 of the ClinGen PTEN Expert Panel Version 3.2 framework, one very strong pathogenic criterion plus two moderate criteria or one supporting criterion yields Likely Pathogenic; here PVS1 very strong plus PM2 supporting is the matched combination.

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: the frameshift truncates PTEN at p.Ser338, before the VCEP p.D375 (c.1121) NMD threshold in transcript NM_000314.8.	cspec vcep_pvs1_decisiontree_pten
PS1	N/A	Not applicable: c.1012_1016del is a frameshift, p.(S338Kfs*3), rather than a missense amino-acid substitution required for this PS1 comparison.	cspec
PS2	Not assessed	Not assessed: no proband diagnosis, parental testing, maternity/paternity confirmation, or family-history documentation is available for this variant.	cspec
PS3	N/A	Not applicable: the PTEN VCEP functional rule covers high-confidence missense assay entries, whereas this variant is a frameshift absent under all three searched notations.	cspec vcep_mmc2 PMID:11237521 PMID:17218262
PS4	Not assessed	Not assessed: no variant-specific case-control enrichment or phenotype-specificity score is available for comparison with the PTEN PS4 thresholds.	cspec
PM1	Not met	Not met: the variant begins at residue 338, outside the PTEN VCEP PM1 catalytic-motif intervals 90–94, 123–130, and 166–168.	cspec PMID:11237521
PM2	Met	Met, Supporting: the variant is absent from gnomAD v2.1 and v4.1, meeting the PTEN PM2 threshold below 0.00001 (0.001%).	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN VCEP specification explicitly designates PM3 as not applicable for this autosomal-dominant disorder.	cspec
PM4	N/A	Not applicable: the variant is a frameshift with a premature stop, whereas PTEN PM4 covers in-frame length changes or stop-loss extensions.	cspec
PM5	N/A	Not applicable: PM5 requires a missense change at a residue with a pathogenic or likely pathogenic alternate missense change, whereas this variant is a frameshift.	cspec
PM6	Not assessed	Not assessed: no assumed de novo observation, parental results, proband diagnosis, family history, or independent occurrence count is documented.	cspec
PP1	Not assessed	Not assessed: no affected relatives, segregation results, phase information, or meiosis count is documented for this variant.	cspec
PP2	N/A	Not applicable: the PTEN VCEP PP2 rule is missense-specific, while this variant is the frameshift p.(S338Kfs*3).	cspec
PP3	N/A	Not applicable: the variant is a frameshift, p.(S338Kfs*3), outside PP3's calibrated missense and splice-impact scope.	cspec
PP4	N/A	Not applicable: the PTEN VCEP incorporates phenotype specificity into PS4 and marks PP4 as not applicable.	cspec
PP5	N/A	Not applicable: the PTEN VCEP excludes PP5, and ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic classification.	cspec clinvar
BA1	Not met	Not met: gnomAD v2.1 and v4.1 report the variant absent, not a filtering allele frequency greater than 0.00056 (0.056%).	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 report absence, with no allele frequency in the PTEN BS1 range of 0.0000043 to 0.00056.	cspec gnomad_v2 gnomad_v4
BS2	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with no reported homozygous healthy individual.	cspec gnomad_v2 gnomad_v4
BS3	N/A	Not applicable: the PTEN VCEP benign functional rules require applicable missense or splicing assay evidence, but this frameshift has no exact entry under the searched variant notations.	cspec vcep_mmc2 PMID:11237521 PMID:17218262
BS4	Not assessed	Not assessed: no affected family members or variant-testing results demonstrate non-segregation in one or more families.	cspec
BP1	N/A	Not applicable: the PTEN VCEP explicitly marks BP1 as not applicable, and this case variant is a truncating frameshift rather than a missense variant.	cspec
BP2	Not assessed	Not assessed: no second pathogenic PTEN variant or cis/trans phase observation is available to meet the VCEP BP2 rule.	cspec
BP3	N/A	Not applicable: the PTEN VCEP marks BP3 as not applicable, and this variant is a truncating frameshift rather than a repeat-region in-frame deletion.	cspec
BP4	N/A	Not applicable: the variant is a frameshift, p.(S338Kfs*3), outside BP4's calibrated missense and splice-impact scope.	cspec
BP5	Not assessed	Not assessed: no two qualifying cases with a highly penetrant alternate diagnosis and non-overlapping PTEN histories are documented.	cspec
BP6	N/A	Not applicable: the PTEN VCEP excludes BP6, and ClinVar has no exact-variant expert-panel Benign or Likely benign classification.	cspec clinvar
BP7	N/A	Not applicable: the variant is a frameshift, p.(S338Kfs*3), not the synonymous variant required for BP7.	cspec

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