LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_000314.8:c.256G>C
PTEN
· NP_000305.3:p.(Ala86Pro)
· NM_000314.8
GRCh37: chr10:89692772 G>C
·
GRCh38: chr10:87933015 G>C
Gene:
PTEN
Transcript:
NM_000314.8
Final call
VUS
PS3_Moderate
PM2_Supporting
PP2
PP3
Variant details
Gene
PTEN
Transcript
NM_000314.8
Protein
NP_000305.3:p.(Ala86Pro)
gnomAD AF
ClinVar
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PTEN final classification was assigned using the explicit CSPEC/VCEP criteria-combination framework rather than generic ACMG/AMP combination rules.
2
The applicable pathogenic evidence consists of PS3_Moderate, PM2_Supporting, PP2, and PP3.
3
This combination provides 1 Moderate and 3 Supporting pathogenic criteria, which does not match a defined PTEN rule for Likely Pathogenic or Pathogenic.
4
No benign standalone, strong, or supporting rule combination is satisfied, so the variant remains of uncertain significance.
Final determination:
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 | PTEN-specific PVS1 guidance in the workspace applies to null variants, canonical splice-site variants, frameshifts, nonsense variants, and CNVs. NM_000314.8:c.256G>C is a missense substitution encoding p.(Ala86Pro), so the PTEN PVS1 decision tree does not apply. |
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/prefetch.json
/Users/gs_agent/LYFESCI_HERMES_v7/vcep_db/PTEN/files/index.txt
|
| PS1 | Not assessed | PTEN EP PS1 requires the same amino acid change as a previously established pathogenic variant. The assembled workspace does not provide a qualifying previously established pathogenic alternate nucleotide producing p.Ala86Pro, and ClinVar is empty for this variant. No same-amino-acid pathogenic comparator was documented in the workspace. |
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/case_summary.json
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/evidence.json
|
| PS2 | Not assessed | No proband-level de novo evidence, parental testing, or family history information is present in the workspace. |
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/case_summary.json
|
| PS3 | Met | The PTEN EP specifies PS3_Moderate for Mighell et al. 2018 phosphatase activity score <= -1.11. In local mmc2.xlsx Table S2, A86P / Ala86Pro has Cum_score -2.188961661 with High_conf = True, satisfying PS3_Moderate. |
/Users/gs_agent/LYFESCI_HERMES_v7/vcep_db/PTEN/files/mmc2.xlsx
/Users/gs_agent/LYFESCI_HERMES_v7/vcep_db/PTEN/files/index.txt
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/prefetch.json
|
| PS4 | Not assessed | PTEN EP PS4 requires germline proband enrichment or phenotype-specific proband scoring. The workspace contains no PHTS-specific germline case series, no scored probands, and only a single somatic COSMIC observation, which is not sufficient for PTEN germline PS4. |
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/evidence.json
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/literature_pass.json
|
| PM1 | Not met | PTEN EP PM1 is restricted to catalytic motif residues 90-94, 123-130, and 166-168 (NP_000305.3). The variant affects residue Ala86, which is outside the defined motifs, and the workspace hotspot review reports no statistically significant hotspot at A86. |
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/case_summary.json
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/evidence.json
|
| PM2 | Met | PTEN EP downgrades PM2 to Supporting for variants absent or extremely rare in large population datasets. This variant is absent from both gnomAD v2.1 and gnomAD v4.1 in the workspace, satisfying PM2_Supporting. |
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/evidence.json
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/case_summary.json
|
| PM3 | N/A | The PTEN EP marks PM3 as not applicable. |
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/case_summary.json
|
| PM4 | N/A | PTEN EP PM4 is for in-frame insertions/deletions affecting specified contexts or stop-loss/protein-extension variants. NM_000314.8:c.256G>C is a missense substitution and does not change protein length. |
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/prefetch.json
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/case_summary.json
|
| PM5 | Not assessed | PTEN EP PM5 requires a different pathogenic/likely pathogenic missense change at the same residue with appropriate BLOSUM62 comparison. The assembled workspace does not provide a qualifying established pathogenic missense comparator at Ala86. |
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/case_summary.json
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/literature_pass.json
|
| PM6 | Not assessed | No assumed de novo case information is present in the workspace. |
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/case_summary.json
|
| PP1 | Not assessed | No segregation data or meiosis counts are present in the workspace. |
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/case_summary.json
|
| PP2 | Met | PTEN EP retains PP2 for missense variants in PTEN because missense variation is a common disease mechanism in a gene with low benign missense variation. This variant is a missense substitution, p.(Ala86Pro), so PP2 is met at Supporting strength. |
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/case_summary.json
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/prefetch.json
|
| PP3 | Met | For PTEN missense variants, PP3 applies when REVEL > 0.7. The workspace reports REVEL 0.945 for this variant, satisfying PP3. |
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/evidence.json
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/prefetch.json
|
| PP4 | N/A | The PTEN EP marks PP4 as not applicable because phenotype specificity has been incorporated into PS4 specifications. |
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/case_summary.json
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/prefetch.json
|
| PP5 | N/A | The PTEN EP marks PP5 as not applicable. |
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/case_summary.json
|
| BA1 | Not met | PTEN EP BA1 requires filtering allele frequency >0.00056. The variant is absent from both gnomAD v2.1 and gnomAD v4.1, so BA1 is not met. |
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/evidence.json
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/case_summary.json
|
| BS1 | Not met | PTEN EP BS1 requires allele frequency within benign threshold ranges. The variant is absent from both gnomAD releases in the workspace, so BS1 is not met. |
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/evidence.json
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/case_summary.json
|
| BS2 | Not met | PTEN EP BS2 requires homozygous observation(s) in healthy/PHTS-unaffected individuals. No such homozygous or unaffected-control observations are documented in the assembled workspace. |
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/evidence.json
|
| BS3 | Not met | PTEN EP BS3_Supporting for missense variants requires phosphatase activity >0 in Mighell et al. 2018, or other functional evidence showing no damaging effect. In local mmc2.xlsx Table S2, A86P has Cum_score -2.188961661 with High_conf = True, indicating damaging function rather than benign function. Therefore BS3 is not met. |
/Users/gs_agent/LYFESCI_HERMES_v7/vcep_db/PTEN/files/mmc2.xlsx
/Users/gs_agent/LYFESCI_HERMES_v7/vcep_db/PTEN/files/index.txt
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/prefetch.json
|
| BS4 | Not assessed | No family-based lack-of-segregation evidence is present in the workspace. |
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/case_summary.json
|
| BP1 | N/A | The PTEN EP marks BP1 as not applicable. |
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/case_summary.json
|
| BP2 | Not assessed | No phasing data or observations with other pathogenic PTEN variants are present in the workspace. |
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/case_summary.json
|
| BP3 | N/A | The PTEN EP marks BP3 as not applicable. |
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/case_summary.json
|
| BP4 | Not met | For PTEN missense variants, BP4 requires REVEL <0.5. The workspace REVEL score is 0.945, which is incompatible with BP4. Low SpliceAI does not rescue BP4 here because the missense-specific REVEL rule is not met. |
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/evidence.json
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/case_summary.json
|
| BP5 | Not assessed | No alternate molecular diagnosis or phenotype-overlap analysis is present in the workspace. |
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/case_summary.json
|
| BP6 | N/A | The PTEN EP marks BP6 as not applicable. |
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/case_summary.json
|
| BP7 | N/A | PTEN EP BP7 applies to synonymous or qualifying intronic variants with no predicted splice impact. NM_000314.8:c.256G>C is a missense substitution, so BP7 is not applicable. |
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/case_summary.json
/Users/gs_agent/LYFESCI_HERMES_v7/cases/NM_000314.8_c.256G_C_20260414_021027/output/evidence.json
|
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.