Variant classification summary

NM_000314.8:c.488_492+5del

PTEN · NP_000305.3:p.? · NM_000314.8

GRCh37: chr10:89693003 AAAAAGGTAAG>A · GRCh38: chr10:87933246 AAAAAGGTAAG>A

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PM2 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: the variant is absent from gnomAD v2.1, v4.1, and available non-cancer subsets.

Final determination: No PTEN Expert Panel Version 3.2 criteria-combination rule matched the adjudicated evidence consisting only of PM2 supporting, so the variant remains a VUS.

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	Not assessed	Not assessed: SpliceAI max delta 0.994 predicts splice impact, but the resulting reading-frame consequence and NMD outcome are unestablished.	cspec vcep_pvs1_decisiontree_pten spliceai
PS1	Not assessed	Not assessed: the intronic variant has protein consequence p.? and no established pathogenic same-amino-acid or same-position splice comparator is available.	cspec
PS2	Not assessed	Not assessed: no proband, parental-testing, maternity/paternity, or family-history data are available to establish a confirmed de novo occurrence.	cspec
PS3	Not assessed	Not assessed: no RNA or minigene assay result is available, and the governing missense phosphatase table contains no entry for this p.? splice-region deletion.	cspec vcep_mmc2
PS4	Not assessed	Not assessed: no case-control odds ratio is available to compare with the PTEN PS4 >2 threshold.	cspec
PM1	N/A	Not applicable: c.488_492+5del is an intronic splice-region deletion with protein consequence p.?, not a residue-level change in a PTEN catalytic motif.	cspec
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1, v4.1, and non-cancer subsets, below the PTEN PM2 threshold of <0.00001 allele frequency.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN VCEP version 3.2 explicitly designates PM3 as not applicable for this autosomal-dominant disorder.	cspec
PM4	N/A	Not applicable: p.? provides no established in-frame protein-length change or stop-loss extension required by the PTEN PM4 rule.	cspec
PM5	N/A	Not applicable: the variant is an intronic splice-region deletion with protein consequence p.?, not a missense change eligible for same-residue PM5.	cspec
PM6	Not assessed	Not assessed: no affected proband, assumed de novo observation, parental-testing, or family-history data are available for PM6.	cspec
PP1	Not assessed	Not assessed: no affected relatives, segregation observations, family structure, or meiosis count are available for comparison with the 3-meiosis minimum.	cspec
PP2	N/A	Not applicable: PP2 is restricted to missense variants, whereas c.488_492+5del is an intronic splice-region deletion with protein consequence p.?.	cspec
PP3	Not assessed	Not assessed: SpliceAI max delta 0.994 exceeds 0.5, but the PTEN VCEP requires concordant SpliceAI and VarSeak results and VarSeak is unavailable.	cspec spliceai
PP4	N/A	Not applicable: the PTEN Expert Panel incorporates phenotype specificity into PS4 Use 2 rather than allowing independent PP4.	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: the variant is absent from gnomAD v2.1, gnomAD v4.1, and non-cancer subsets, versus the PTEN BA1 threshold of >0.00056 allele frequency.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from all queried gnomAD datasets, versus the PTEN BS1 range of 0.0000043 to 0.00056 allele frequency.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no homozygous observation in a healthy or PHTS-unaffected individual is available to compare with the PTEN BS2 requirement.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no benign RNA or minigene assay result is available, and the governing missense phosphatase table contains no entry for this p.? splice-region deletion.	cspec vcep_mmc2
BS4	Not assessed	Not assessed: no affected-family-member genotypes or non-segregation observations are available to establish BS4 in one or more families.	cspec
BP1	N/A	Not applicable: the PTEN VCEP excludes BP1, and this variant is intronic with protein consequence p.? rather than missense.	cspec
BP2	Not assessed	Not assessed: no phase-resolved observation shows this variant in trans with a pathogenic PTEN variant or satisfies the three-observation cis/unknown-phase rule.	cspec
BP3	N/A	Not applicable: the PTEN VCEP explicitly marks BP3 as Not Applicable, and this variant is not an established in-frame repeat-region deletion.	cspec
BP4	Not met	Not met: SpliceAI max delta 0.994 indicates splice impact and exceeds the <=0.1 BP4 threshold.	cspec spliceai
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 an intronic splice-region deletion, whereas BP7 applies only to synonymous variants.	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.