Variant classification summary

NM_000314.8:c.-491_-486dup

PTEN · NP_000305.3:p.? · NM_000314.8

GRCh37: chr10:89623724 A>AGCGGCG · GRCh38: chr10:87863967 A>AGCGGCG

Gene: PTEN Transcript: NM_000314.8

Final call

Benign

BA1 stand-alone benign BS2 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.?

gnomAD AF

0.001393968304446918 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Benign: gnomAD v4.1 allele frequency 0.001394 exceeds the PTEN BA1 threshold of >0.00056.

2

Benign evidence: gnomAD v4.1 reports three homozygous observations, meeting PTEN BS2 supporting criteria.

Final determination: Under Rule17 of the ClinGen PTEN Expert Panel Version 3.2 framework, one met BA1 stand-alone benign criterion is sufficient for a Benign 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	N/A	Not applicable: the six-base 5' UTR GGC-repeat duplication has predicted protein consequence NP_000305.3:p.(=), not a coding loss-of-function change.	cspec vcep_pvs1_decisiontree_pten
PS1	N/A	Not applicable: the 5' UTR insertion has protein consequence p.? and therefore no amino-acid change for PS1 comparison.	cspec
PS2	Not assessed	Not assessed: no documented de novo proband or parental testing was available to satisfy the PTEN PS2 requirement for confirmed maternity and paternity.	cspec
PS3	Not assessed	Not assessed: mmc2.xlsx has no entry for c.-491_-486dup, p.?, or p.(=), and no qualifying variant-specific functional assay result is available.	cspec vcep_mmc2
PS4	Not assessed	Not assessed: no exact-variant case-control odds ratio, p value, confidence interval, or PTEN phenotype-specific proband score is available for comparison with the PS4 thresholds.	cspec gnomad_v4
PM1	N/A	Not applicable: the 5' UTR insertion has no protein residue, whereas PTEN PM1 requires residues 90-94, 123-130, or 166-168.	cspec
PM2	Not met	Not met: gnomAD v4.1 AF 0.001394 is far above the PTEN PM2 threshold of <0.00001.	cspec gnomad_v4 gnomad_v2
PM3	N/A	Not applicable: the PTEN VCEP version 3.2 explicitly designates PM3 as not applicable.	cspec
PM4	Not met	Not met: predicted protein consequence NP_000305.3:p.(=) shows no protein-length change, and the variant is upstream of all PTEN catalytic motifs.	cspec
PM5	N/A	Not applicable: the 5' UTR insertion is not missense and has protein consequence p.?, so no same-residue PM5 comparison is possible.	cspec pm5_candidates
PM6	Not assessed	Not assessed: zero documented assumed de novo observations were available against the PTEN PM6 minimum of one disease proband without confirmed maternity and paternity.	cspec
PP1	Not assessed	Not assessed: zero informative meioses or affected relatives were documented, below the PTEN PP1 Supporting threshold of 3 or 4 meioses.	cspec
PP2	N/A	Not applicable: PP2 requires a missense variant, but this 5' UTR insertion has protein consequence p.?.	cspec
PP3	N/A	Not applicable: the upstream c.-491_-486 duplication has protein consequence p.? and is outside PP3's missense or intronic/splice-region scope.	cspec
PP4	N/A	Not applicable: the PTEN Expert Panel specification incorporates phenotype specificity into PS4 and explicitly excludes independent PP4 use.	cspec
PP5	N/A	Not applicable: no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification exists, and PTEN VCEP marks PP5 unavailable.	cspec clinvar
BA1	Met	Met: gnomAD v4.1 all-comers AF 0.001394 exceeds the PTEN BA1 threshold of >0.00056.	cspec gnomad_v4 gnomad_v2
BS1	Not met	Not met: gnomAD v4.1 AF 0.001394 is above the PTEN BS1 upper limit of 0.00056 and meets BA1 instead.	cspec gnomad_v4 gnomad_v2
BS2	Met	Met at supporting strength: gnomAD v4.1 reports three homozygotes, exceeding the PTEN rule requiring two observations without clinical data.	cspec gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: mmc2.xlsx has no entry for c.-491_-486dup, p.?, or p.(=), and no qualifying benign functional or splicing assay result is available.	cspec vcep_mmc2
BS4	Not assessed	Not assessed: no affected-family segregation comparison was documented, while the PTEN BS4 Supporting threshold requires lack of segregation in one family.	cspec
BP1	N/A	Not applicable: the PTEN VCEP marks BP1 not applicable, and this 5' UTR insertion is not a missense variant.	cspec
BP2	Not met	Not met: no documented trans observation or at least three cis/unknown-phase observations with pathogenic or likely pathogenic PTEN variants.	cspec clinvar
BP3	N/A	Not applicable: the PTEN VCEP Version 3.2 specification explicitly designates BP3 as not applicable.	cspec
BP4	N/A	Not applicable: the upstream c.-491_-486 duplication has protein consequence p.? and is outside BP4's missense or intronic/splice-region scope.	cspec
BP5	Not assessed	Not assessed: no two qualifying cases with a highly penetrant alternate molecular diagnosis and non-overlapping personal or family history are documented.	cspec
BP6	N/A	Not applicable: no exact-variant ClinVar expert-panel Benign or Likely benign classification exists, and PTEN VCEP marks BP6 unavailable.	cspec clinvar
BP7	N/A	Not applicable: the upstream c.-491_-486 duplication is not annotated as synonymous or intronic, so BP7's scope does not apply.	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.