Variant classification summary

NM_000314.8:c.758_760dup

PTEN · NP_000305.3:p.(Ile253dup) · NM_000314.8

GRCh37: chr10:89717731 T>TATC · GRCh38: chr10:87957974 T>TATC

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PM2 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Ile253dup)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1, meeting the PTEN population-frequency threshold.

Final determination: No pathogenic, likely pathogenic, benign, or likely benign combination rule was satisfied; PM2 supporting alone therefore results in a VUS under the PTEN Expert Panel Version 3.2 framework.

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	N/A	Not applicable: p.(Ile253dup) is an in-frame one-residue insertion, not a PTEN null variant eligible for the VCEP PVS1 decision tree.	cspec vcep_pvs1_decisiontree_pten
PS1	N/A	Not applicable: p.Ile253dup is an in-frame duplication, not a missense amino-acid substitution eligible for the PTEN PS1 rule.	cspec clinvar
PS2	Not assessed	Not assessed: no documented proband phenotype, parental testing, maternity/paternity confirmation, or family-history information establishes a proven de novo occurrence.	cspec
PS3	Not assessed	Not assessed: the governing assay contains no c.758_760dup, p.Ile253dup, or p.I253dup entry, and the variant is an in-frame duplication rather than a tested missense substitution.	cspec vcep_mmc2
PS4	Not assessed	Not assessed: no case-control enrichment, proband phenotype, family history, or PTEN phenotype-specificity score was reported for this variant.	cspec
PM1	Not met	Not met: residue 253 lies outside PTEN catalytic motifs 90–94, 123–130, and 166–168, and no hotspot was identified.	cspec
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, satisfying the PTEN PM2 absence threshold of <0.00001.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN VCEP Version 3.2 explicitly excludes PM3 for this autosomal-dominant disorder.	cspec
PM4	Not met	Not met: p.(Ile253dup) adds one residue at 253, outside PTEN catalytic motifs 90-94, 123-130, and 166-168, and does not cause protein extension.	cspec
PM5	N/A	Not applicable: p.Ile253dup is an in-frame duplication, whereas the PTEN PM5 rule requires a different pathogenic missense change at the same residue.	cspec pm5_candidates
PM6	Not assessed	Not assessed: no documented assumed de novo observation, proband disease phenotype, family-history status, or count of independent de novo occurrences supports PM6.	cspec
PP1	Not assessed	Not assessed: no affected relatives, co-segregation results, or meioses are documented to meet the PTEN VCEP minimum of 3 meioses.	cspec
PP2	N/A	Not applicable: the queried alteration is an in-frame duplication, while the PTEN VCEP PP2 rule is restricted to missense variants.	cspec
PP3	N/A	Not applicable: c.758_760dup is an in-frame duplication producing p.(Ile253dup), not a missense or splice-region/intronic variant within PP3 scope.	cspec
PP4	N/A	Not applicable: the PTEN Expert Panel incorporates phenotype specificity into PS4 rather than allowing independent PP4 use.	cspec
PP5	N/A	Not applicable: PP5 is excluded by the PTEN Expert Panel and this exact variant has no ClinVar expert-panel Pathogenic or Likely pathogenic classification.	cspec clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so its frequency does not exceed the PTEN BA1 threshold of 0.00056.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than having a PTEN BS1-range frequency of 0.0000043 to 0.00056.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports no variant observation and supplies no homozygote count or healthy-individual genotype evidence for the PTEN BS2 rule.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: the governing assay has no c.758_760dup, p.Ile253dup, or p.I253dup result, so no benign functional value is available for this in-frame duplication.	cspec vcep_mmc2
BS4	Not assessed	Not assessed: no affected-family testing or non-segregation observations are documented for one family or for two or more families.	cspec
BP1	N/A	Not applicable: the PTEN VCEP marks BP1 Not Applicable, and this alteration is an in-frame duplication rather than a missense variant.	cspec
BP2	Not assessed	Not assessed: no documented cis/trans phase observation with a pathogenic or likely pathogenic PTEN variant is available.	cspec
BP3	N/A	Not applicable: the PTEN CSPEC explicitly designates BP3 as Not Applicable for PTEN variant interpretation.	cspec
BP4	N/A	Not applicable: c.758_760dup is an in-frame duplication producing p.(Ile253dup), not a missense or splice-region/intronic variant within BP4 scope.	cspec
BP5	Not assessed	Not assessed: no qualifying alternate molecular diagnosis in at least two cases or non-overlapping personal and family history was reported.	cspec
BP6	N/A	Not applicable: BP6 is excluded by the PTEN Expert Panel and this exact variant has no ClinVar expert-panel Benign or Likely benign classification.	cspec clinvar
BP7	N/A	Not applicable: c.758_760dup produces p.(Ile253dup), so it is not a synonymous variant within BP7 scope.	cspec

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