PTEN c.70G>A, p.(Asp24Asn)

Rule

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

Evidence considered

• mmc2.xlsx Table S2: D24N, Cum_score -1.549791026
• High_conf: true (Pass SE Filter)
• PTEN CSPEC PS3_Moderate threshold: phosphatase activity score <= -1.11

Sources

Rule

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

Evidence considered

• Absent from gnomAD v2.1
• Absent from gnomAD v4.1

Sources

Rule

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

Evidence considered

• Variant class: missense
• PTEN CSPEC includes PP2 for missense variants

Sources

Rule

PTEN CSPEC PP3: missense variants with REVEL > 0.7.

Evidence considered

• REVEL score 0.753
• PTEN CSPEC PP3 threshold for missense: REVEL > 0.7
• SpliceAI max delta 0.02

Sources

Rule

PTEN CSPEC PS1: same amino acid change as a previously established pathogenic variant regardless of nucleotide change.

Evidence considered

• Table S3 includes PTEN c.70G>A (p.Asp24Asn) but no different nucleotide change yielding p.Asp24Asn

Still missing

• No alternate nucleotide encoding p.Asp24Asn was identified in the reviewed local sources.

Sources

Rule

PTEN CSPEC PM1: only residues in catalytic motifs 90-94, 123-130, 166-168.

Evidence considered

• Protein position: Asp24
• PTEN PM1 restricted to catalytic motifs 90-94, 123-130, 166-168
• Hotspot noted, but PTEN CSPEC PM1 is domain-restricted

Sources

Rule

PTEN CSPEC PM5: different pathogenic/likely pathogenic missense at same residue and queried variant must have BLOSUM62 score equal to or less than known variant.

Evidence considered

• Table S3: c.70G>C p.Asp24His Pathogenic
• Table S3: c.70G>T p.Asp24Tyr Pathogenic
• Table S3: c.71A>G p.Asp24Gly Pathogenic
• BLOSUM62 scores: D>N=1, D>H=-1, D>Y=-3, D>G=-1

Sources

Rule

PTEN CSPEC BA1: filtering allele frequency >0.00056.

Evidence considered

• Absent from gnomAD v2.1
• Absent from gnomAD v4.1

Sources

Rule

PTEN CSPEC BS1: allele frequency within PTEN BS1 supporting or strong benign ranges.

Evidence considered

• Absent from gnomAD v2.1
• Absent from gnomAD v4.1

Sources

Rule

PTEN CSPEC BS3_Supporting requires phosphatase activity >0; BS3 requires functional studies showing no damaging effect.

Evidence considered

• mmc2.xlsx Table S2: D24N Cum_score -1.549791026, High_conf true

Sources

Rule

PTEN CSPEC BP4: missense variants with REVEL < 0.5.

Evidence considered

• REVEL score 0.753

Sources

Rule

PTEN CSPEC PS2: confirmed de novo occurrence in a patient with disease and no family history.

Evidence considered

• No de novo observation extracted

Still missing

• No maternity/paternity-confirmed de novo observation available.

Sources

Rule

PTEN CSPEC PS4 requires proband specificity scoring or significant prevalence increase in affected individuals versus controls.

Evidence considered

• ClinVar pathogenic submissions present
• Multiple literature PMIDs listed without extractable PS4 scoring details

Still missing

• No scored PTEN proband count/specifity score extracted.
• No germline case-control comparison extracted.

Sources

Rule

PTEN CSPEC PM6: assumed de novo occurrence in a proband with disease and no family history.

Evidence considered

• No PM6-relevant case data extracted

Still missing

• No assumed de novo case information available.

Sources

Rule

PTEN CSPEC PP1: cosegregation with disease in informative meioses.

Evidence considered

• No segregation evidence extracted

Still missing

• No informative meioses or familial segregation data available.

Sources

Rule

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

Evidence considered

• Variant absent from gnomAD; no homozygous unaffected data extracted

Still missing

• No homozygous unaffected observations available.

Sources

Rule

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

Evidence considered

• No BS4-relevant segregation evidence extracted

Still missing

• No family data demonstrating lack of segregation.

Sources

Rule

PTEN CSPEC BP2: observed in trans with a pathogenic PTEN variant, or at least three cis/phase-unknown observations with different pathogenic PTEN variants.

Evidence considered

• No BP2-relevant phase data extracted

Still missing

• No in trans, in cis, or phase-unknown observations with another pathogenic PTEN variant.

Sources

Rule

PTEN CSPEC BP5: alternate molecular basis for disease with no phenotype overlap with PTEN-related disease.

Evidence considered

• No BP5-relevant alternate diagnosis extracted

Still missing

• No alternate molecular explanation documented.

Sources