Variant classification summary

NM_000314.8:c.387dup

PTEN · NP_000305.3:p.(Arg130ThrfsTer50) · NM_000314.8

GRCh37: chr10:89692902 G>GA · GRCh38: chr10:87933145 G>GA

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.(Arg130ThrfsTer50)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: c.387dup causes a p.Arg130 frameshift upstream of the PTEN NMD threshold, meeting PVS1 very strong.

2

Pathogenic: the frameshift begins within the PTEN catalytic motif at residues 123-130, meeting PM1 moderate.

3

Pathogenic: the variant is absent from gnomAD v2.1 and v4.1, meeting PM2 supporting.

Final determination: Under Rule3 of the ClinGen PTEN Expert Panel Version 3.2 framework, one Pathogenic Very Strong criterion, one Pathogenic Moderate criterion, and one Pathogenic Supporting criterion combine to yield a Pathogenic classification.

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: the p.Arg130 frameshift is 5' of PTEN p.D375 (c.1121), so the decision tree assigns this NM_000314.8 variant full PVS1 for predicted NMD.	cspec vcep_pvs1_decisiontree_pten
PS1	N/A	Not applicable: c.387dup is a frameshift (p.Arg130ThrfsTer50), not a missense change eligible for same-amino-acid PS1.	cspec
PS2	Not assessed	Not assessed: no documented proband phenotype, parental testing, maternity/paternity confirmation, or de novo observation is available for this variant.	cspec
PS3	N/A	Not applicable: the PTEN VCEP assay rule covers missense variants, whereas c.387dup produces the frameshift p.Arg130ThrfsTer50 and has no matching assay entry.	cspec vcep_mmc2
PS4	Not assessed	Not assessed: no case-control odds ratio or PTEN phenotype-specific proband score is available to compare with the VCEP PS4 thresholds.	cspec
PM1	Met	Met, moderate: the frameshift starts at Arg130, within the PTEN VCEP catalytic-motif interval 123-130 for PM1.	cspec
PM2	Met	Met at Supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the PTEN PM2 requirement of frequency <0.00001.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN VCEP marks PM3 as not applicable for this autosomal-dominant disorder.	cspec
PM4	N/A	Not applicable: c.387dup creates a frameshift and premature termination, whereas PTEN PM4 is limited to in-frame length changes or stop-loss variants.	cspec
PM5	N/A	Not applicable: c.387dup is a frameshift, whereas PTEN PM5 requires a missense change and a same-residue missense comparator.	cspec pm5_candidates
PM6	Not assessed	Not assessed: no specific de novo report, affected proband phenotype, family history, or parental-testing information is documented for this variant.	cspec
PP1	Not assessed	Not assessed: no affected relatives, segregation results, family structure, or meiosis count is documented for this variant.	cspec
PP2	N/A	Not applicable: PP2 is restricted to missense variants, while c.387dup produces the frameshift p.Arg130ThrfsTer50.	cspec
PP3	N/A	Not applicable: c.387dup is a frameshift, outside PP3's missense, intronic, synonymous, and splice-region scope.	cspec
PP4	N/A	Not applicable: the PTEN VCEP incorporates phenotype specificity into PS4 rather than allowing independent PP4 use.	cspec
PP5	N/A	Not applicable: PP5 is prohibited by the PTEN VCEP, and this exact variant has no ClinVar expert-panel classification.	cspec clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with frequency 0 versus the PTEN BA1 threshold >0.00056.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with frequency 0 below the PTEN BS1 Supporting lower bound of 0.0000043.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports no observations of the variant, so no confirmed healthy homozygote is available for the PTEN BS2 requirement.	cspec gnomad_v2 gnomad_v4
BS3	N/A	Not applicable: the PTEN VCEP assay rule covers missense variants, whereas c.387dup produces the frameshift p.Arg130ThrfsTer50 and has no matching assay entry.	cspec vcep_mmc2
BS4	Not assessed	Not assessed: no affected-family testing or documented non-segregation observation is available for this variant.	cspec
BP1	N/A	Not applicable: the PTEN VCEP marks BP1 not applicable, and c.387dup is a frameshift rather than a missense variant.	cspec
BP2	Not assessed	Not assessed: no qualifying trans observation or three cis/phase-unknown observations with different pathogenic PTEN variants are documented.	cspec
BP3	N/A	Not applicable: c.387dup is a premature-termination frameshift, while the PTEN specification marks BP3 not applicable for this consequence.	cspec
BP4	N/A	Not applicable: c.387dup is a frameshift, outside BP4's missense, intronic, synonymous, and splice-region scope.	cspec
BP5	Not assessed	Not assessed: no qualifying alternate molecular diagnosis, two-case minimum, or non-overlapping PTEN history is documented for BP5.	cspec
BP6	N/A	Not applicable: BP6 is prohibited by the PTEN VCEP, and this exact variant has no ClinVar expert-panel benign classification.	cspec clinvar
BP7	N/A	Not applicable: c.387dup is a frameshift, not a synonymous variant required for BP7.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.