LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-16
Case ID: NM_000314.8_c.527A_G_20261016_023136
Framework: ACMG/AMP 2015
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 moderate PM6 moderate PP2 supporting BS1 strong
All criteria require review: For research and educational purposes only.
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 Moderate: Y176C has a directly measured phosphatase-assay Cum_score of -1.291488163, below the PTEN VCEP damaging threshold.
2
PM6 Moderate: Y176C was absent from both tested parents, supporting an assumed de novo observation with unconfirmed maternity.
3
PP2 Supporting: PTEN missense variation is an established disease mechanism in a gene with a low rate of benign missense variation.
4
BS1 Strong: the maximum gnomAD Filtering allele frequency of 7.354e-05 lies within the PTEN VCEP BS1 Strong range.
Final determination: Under Rule20 of the ClinGen PTEN Expert Panel Version 3.2 framework, one adjudicated BS1 Strong criterion is sufficient for a Likely Benign call.
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 variant, whereas the PTEN PVS1 decision tree covers null, splice-site, and copy-number loss-of-function variants.
cspec vcep_pvs1_decisiontree_pten pvs1_variant_assessment
PS1 Not assessed Not assessed: Y176C is reported, but no clearly established pathogenic classification for the same amino-acid change is documented.
cspec PMID:18759867 PMID:21659347 PMID:21828076 PMID:25647146
PS2 Not met Not met: both-parent absence was reported, but only alleged paternity was confirmed, not both maternity and paternity as required for PS2 Strong.
cspec PMID:18759867
PS3 Met Met at Moderate: Y176C Cum_score -1.291488163 is below the PTEN VCEP PS3 threshold of <= -1.11 in a directly measured saturation-mutagenesis assay.
cspec vcep_mmc2 PMID:25647146
PS4 Not assessed Not assessed: individual reports describe p.Y176C phenotypes, but no case-control statistics or computable PTEN specificity score establish a PS4 threshold.
cspec PMID:18759867 PMID:21659347 PMID:21828076 PMID:25647146
PM1 Not met Not met: Tyr176 is outside the VCEP catalytic-motif intervals 90-94, 123-130, and 166-168.
cspec
PM2 Not met Not met: East Asian gnomAD v4.1 allele frequency is 0.000133761, exceeding the PTEN VCEP PM2 subpopulation limit of 0.00002.
cspec gnomad_v2 gnomad_v4
PM3 N/A Not applicable: the PTEN VCEP framework explicitly excludes PM3 for this autosomal-dominant disorder.
cspec
PM4 N/A Not applicable: p.Tyr176Cys is a single-residue missense substitution and produces no protein length change required by the PTEN PM4 rule.
cspec
PM5 Not assessed Not assessed: no qualifying pathogenic or likely pathogenic alternate missense change at Tyr176 was identified for the required BLOSUM62 comparison.
cspec pm5_candidates
PM6 Met Met at Moderate: p.Y176C was absent from both tested parents, with paternity confirmed, supporting one assumed de novo observation under the PTEN VCEP rule.
cspec PMID:18759867
PP1 Not assessed Not assessed: no multiple affected relatives or informative meiosis count is reported for PP1 co-segregation.
cspec PMID:18759867
PP2 Met Met, supporting: PTEN has an established missense disease mechanism, and the VCEP applies PP2 to missense variants in this gene.
cspec PMID:21194675 PMID:21828076
PP3 Not met Not met: REVEL score 0.695 is below the PTEN VCEP PP3 supporting threshold of >0.7 for missense variants.
cspec revel
PP4 N/A Not applicable: the PTEN Expert Panel incorporates phenotype specificity into PS4 rather than using PP4.
cspec
PP5 N/A Not applicable: no exact-variant ClinVar expert-panel pathogenic or likely-pathogenic classification exists, and the PTEN VCEP does not use PP5.
cspec clinvar
BA1 Not met Not met: maximum gnomAD Filtering allele frequency is 7.354e-05, below the PTEN VCEP BA1 threshold of 0.00056.
cspec gnomad_v2 gnomad_v4
BS1 Met Met at Strong: maximum gnomAD Filtering allele frequency is 7.354e-05, within the PTEN VCEP BS1 Strong interval of 0.000043 to 0.00056.
cspec gnomad_v2 gnomad_v4
BS2 Not met Not met: gnomAD v2.1 and v4.1 report zero homozygotes, so no qualifying healthy homozygous observation is available.
cspec gnomad_v2 gnomad_v4
BS3 Not met Not met: Y176C Cum_score -1.291488163 is not >0, and an independent assay measured only 32% of wild-type phosphatase activity.
cspec vcep_mmc2 PMID:25647146
BS4 Not assessed Not assessed: no affected relatives with documented non-segregation are reported for the BS4 evaluation.
cspec PMID:18759867
BP1 N/A Not applicable: the governing PTEN VCEP explicitly marks BP1 as not applicable.
cspec
BP2 Not assessed Not assessed: no qualifying trans observation or three cis/phase-unknown observations with different pathogenic PTEN variants are documented.
cspec PMID:21659347 PMID:18759867
BP3 N/A Not applicable: PTEN CSPEC v3.2 designates BP3 as not applicable, and p.Tyr176Cys is not a repetitive-region in-frame indel.
cspec
BP4 Not met Not met: REVEL score 0.695 is above the PTEN VCEP BP4 supporting threshold of <0.5 for missense variants.
cspec revel
BP5 Not assessed Not assessed: no two qualifying cases with a highly penetrant alternate diagnosis and non-overlapping PTEN history are documented.
cspec PMID:18759867 PMID:21659347 PMID:25647146
BP6 N/A Not applicable: no exact-variant ClinVar expert-panel benign or likely-benign classification exists, and the PTEN VCEP does not use BP6.
cspec clinvar
BP7 N/A Not applicable: the variant is missense, p.(Tyr176Cys), whereas BP7 is restricted to synonymous or qualifying intronic variants.
cspec
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