PTEN c.256G>C, p.(Ala86Pro)

Rule

PTEN EP PS3_Moderate: phosphatase activity <= -1.11 per Mighell et al. 2018.

Evidence considered

• Local PTEN functional file mmc2.xlsx Table S2 contains row A86P / Ala86Pro.
• Observed values: Cum_score = -2.188961661; High_conf = True.
• PTEN index guidance states PS3_Moderate applies when Cum_score <= -1.11.

Sources

Rule

PTEN EP PM2_Supporting: absent or below PTEN EP frequency thresholds in large population databases.

Evidence considered

• gnomAD v2.1: absent.
• gnomAD v4.1: absent.

Sources

Rule

PTEN EP PP2: missense variant in a gene with low benign missense rate and missense as a common disease mechanism.

Evidence considered

• Variant consequence is missense p.(Ala86Pro).
• PTEN EP explicitly lists PP2 as applicable for missense variation in PTEN.

Sources

Rule

PTEN EP PP3: missense REVEL > 0.7.

Evidence considered

• REVEL score = 0.945.
• PTEN EP PP3 missense threshold is REVEL > 0.7.

Sources

Rule

PTEN EP PM1: missense variant in defined PTEN catalytic motifs.

Evidence considered

• Protein consequence is p.(Ala86Pro).
• PTEN EP PM1 motifs are 90-94, 123-130, and 166-168.
• Cancer Hotspots result: no hotspot row / not a statistically significant hotspot.

Sources

Rule

PTEN EP BA1: AF > 0.056%.

Evidence considered

• gnomAD v2.1: absent.
• gnomAD v4.1: absent.

Sources

Rule

PTEN EP BS1: AF 0.000043-0.00056 (Strong) or 0.0000043-0.000043 (Supporting).

Evidence considered

• gnomAD v2.1: absent.
• gnomAD v4.1: absent.

Sources

Rule

PTEN EP BS2: homozygous observation(s) in healthy/PHTS-unaffected individual(s).

Evidence considered

• Variant is absent from available population datasets in the workspace; no homozygous healthy observations are reported.

Still missing

• Need qualifying homozygous healthy/unaffected observations if BS2 is to be considered.

Sources

Rule

PTEN EP BS3: benign functional evidence; for Mighell assay, BS3_Supporting when phosphatase activity >0.

Evidence considered

• A86P / Ala86Pro in mmc2.xlsx Table S2 has Cum_score = -2.188961661 and High_conf = True.
• PTEN index guidance states BS3_Supporting requires phosphatase activity >0.

Sources

Rule

PTEN EP BP4: missense REVEL < 0.5, or benign splicing predictions for qualifying non-missense contexts.

Evidence considered

• REVEL score = 0.945.
• SpliceAI max delta score = 0.01, but PTEN EP missense BP4 rule is REVEL < 0.5.

Sources

Rule

PTEN EP PS1: same amino acid change as a previously established pathogenic variant.

Evidence considered

• Variant is absent from ClinVar in this workspace.
• No PMID-driven comparator evidence is present in the literature packet.

Still missing

• Explicit review of same-protein-change pathogenic comparators beyond the assembled workspace would be needed to rule PS1 in or out conclusively.

Sources

Rule

PTEN EP PS2: de novo occurrence with phenotype and family-history requirements.

Evidence considered

• Workspace contains molecular normalization and database evidence only; no family-based case data were provided.

Still missing

• Need confirmed or assumed de novo occurrence data in an affected proband with no family history.

Sources

Rule

PTEN EP PS4: phenotype-specific proband scoring or significant enrichment in affected individuals.

Evidence considered

• COSMIC shows one somatic observation (COSV64309575, n=1).
• Literature packet contains no PMIDs or proband evidence.

Still missing

• Need PTEN germline proband counts, phenotype specificity scoring, or statistically increased prevalence in affected individuals versus controls.

Sources

Rule

PTEN EP PM5: different pathogenic missense change at same residue with BLOSUM62 requirement.

Evidence considered

• No comparator publications or ClinVar-based same-residue pathogenic variants are documented in the assembled workspace.

Still missing

• Need explicit same-residue PTEN pathogenic/likely pathogenic comparator review with BLOSUM62 comparison.

Sources

Rule

PTEN EP PM6: assumed/proven de novo evidence with phenotype and family-history requirements.

Evidence considered

• No proband-level de novo metadata were provided.

Still missing

• Need assumed de novo evidence in an affected proband with no family history, or stronger de novo dataset if available.

Sources

Rule

PTEN EP PP1: co-segregation with disease across informative meioses.

Evidence considered

• Workspace lacks pedigree/segregation evidence.

Still missing

• Need family segregation evidence with counted informative meioses.

Sources

Rule

PTEN EP BS4: lack of segregation in affected family members.

Evidence considered

• No pedigree or family segregation records were provided.

Still missing

• Need lack-of-segregation data in one family for BS4_Supporting or two or more families for BS4.

Sources

Rule

PTEN EP BP2: qualifying trans or repeated cis/phase-unknown observations with pathogenic PTEN variants.

Evidence considered

• No phase data were supplied.

Still missing

• Need trans observation with a pathogenic/likely pathogenic PTEN variant, or at least three cis/phase-unknown observations with different pathogenic/likely pathogenic PTEN variants.

Sources

Rule

PTEN EP BP5: alternate molecular basis for disease with no phenotype overlap with PTEN.

Evidence considered

• No alternate molecular basis for disease was documented.

Still missing

• Need evidence of a separate highly penetrant molecular diagnosis with no personal/family-history overlap with PTEN-related disease.

Sources