Variant classification summary

NM_000314.8:c.527A>G

PTEN · NP_000305.3:p.(Tyr176Cys) · NM_000314.8

GRCh37: chr10:89711909 A>G · GRCh38: chr10:87952152 A>G

Gene: PTEN Transcript: NM_000314.8

Final call

Likely Benign

PS3 supporting BS1 strong

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Tyr176Cys)

gnomAD AF

4.9594256985041135e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: Y176C retained 32% of wild-type PTEN phosphatase activity in a controlled biochemical assay.

2

BS1 strong: gnomAD v4.1 filtering allele frequency of 5.79e-05 falls within the PTEN VCEP BS1 strong interval.

Final determination: Under Rule20 of the ClinGen PTEN Expert Panel Version 3.2 framework, one BS1 strong criterion is sufficient for a Likely 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: c.527A>G is a missense p.Tyr176Cys substitution, not a null variant addressed by the PTEN PVS1 decision tree.	cspec vcep_pvs1_decisiontree_pten vcep_mmc2
PS1	Not assessed	PS1 could not be assessed because its agent did not produce valid output.
PS2	Not assessed	Not assessed: the exact-variant report describes one affected boy, but provides no parental testing, confirmed de novo status, or family-history information.	cspec PMID:25647146
PS3	Met	Met at Supporting: recombinant Y176C PTEN retained 32% of wild-type catalytic activity, a 68% reduction meeting the PTEN VCEP functional threshold.	cspec vcep_mmc2 PMID:25647146
PS4	Not met	Not met: one autistic-boy observation lacks the PTEN VCEP's required specificity score of at least 1 point or case-control enrichment.	cspec PMID:25647146
PM1	Not assessed	PM1 could not be assessed because its agent did not produce valid output.
PM2	Not met	Not met: gnomAD v4.1 East Asian AF is 0.000133761, exceeding the PTEN PM2 subpopulation limit of <0.00002.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN Expert Panel specification designates PM3 as not applicable for this autosomal-dominant disorder.	cspec
PM4	N/A	Not applicable: p.Tyr176Cys changes one amino acid but causes no in-frame insertion, deletion, stop-loss, or protein extension required for PTEN PM4.	cspec vcep_mmc2
PM5	Not assessed	PM5 could not be assessed because its agent did not produce valid output.
PM6	Not assessed	Not assessed: one reported boy has the variant, but assumed de novo status, parental testing, and absence of family history are undocumented.	cspec PMID:25647146
PP1	Not assessed	Not assessed: no affected relatives, familial genotypes, co-segregation results, or meioses are reported for c.527A>G.	cspec
PP2	Not assessed	PP2 could not be assessed because its agent did not produce valid output.
PP3	Not met	Not met: missense REVEL score 0.695 does not exceed the PTEN VCEP PP3 supporting threshold of >0.7.	cspec revel
PP4	N/A	Not applicable: the PTEN Expert Panel explicitly designates PP4 as not applicable and incorporates phenotype specificity into PS4.	cspec
PP5	N/A	Not applicable: PTEN does not use PP5, and ClinVar has zero exact-variant expert-panel submissions supporting Pathogenic or Likely pathogenic.	cspec clinvar
BA1	Not met	Not met: maximum gnomAD filtering allele frequency is 7.354e-05, below the PTEN BA1 threshold of >0.00056.	cspec gnomad_v2 gnomad_v4
BS1	Met	Met at strong: gnomAD v4.1 filtering allele frequency 5.79e-05 falls within the PTEN BS1 strong interval 0.000043–0.00056.	cspec gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD v2.1 and v4.1 each report zero homozygotes, with no qualifying healthy-individual homozygous observation.	cspec gnomad_v2 gnomad_v4
BS3	Not met	Not met: Y176C showed 32% of wild-type catalytic activity, not the PTEN VCEP-required absence of a damaging functional effect.	cspec vcep_mmc2 PMID:25647146
BS4	Not assessed	Not assessed: no family testing or documented non-segregation in affected relatives is available for this variant.	cspec
BP1	Not assessed	BP1 could not be assessed because its agent did not produce valid output.
BP2	Not assessed	Not assessed: no qualifying second PTEN variant with documented trans phase or at least three cis/unknown-phase observations is reported for Y176C.	cspec PMID:25647146
BP3	N/A	Not applicable: the PTEN VCEP marks BP3 as Not Applicable, and p.Tyr176Cys is not an in-frame deletion in a repetitive region.	cspec vcep_mmc2
BP4	Not met	Not met: missense REVEL score 0.695 is not below the PTEN VCEP BP4 supporting threshold of <0.5.	cspec revel
BP5	Not assessed	Not assessed: no two qualifying cases with a highly penetrant alternate molecular basis and non-overlapping PTEN history are documented.	cspec
BP6	N/A	Not applicable: PTEN does not use BP6, and the exact variant has no expert-panel Likely benign or Benign classification.	cspec clinvar
BP7	N/A	Not applicable: p.(Tyr176Cys) is a missense change, whereas BP7 is restricted to synonymous or qualifying intronic variants.	cspec

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