Classification rationale

PS3PM2PP3 VUS

PTEN c.209T>G

PS3 (Moderate): Mighell 2018 saturation-mutagenesis cumulative fitness score -4.645 for p.Leu70Arg is far below the -1.11 threshold, indicating severe loss of lipid phosphatase activity. PM2 (Supporting): variant is entirely absent (AF = 0) from gnomAD v2.1, v4.1, and gnomAD-Canada. PP3 (Supporting): REVEL 0.985 exceeds the VCEP cutoff of 0.7, predicting a deleterious missense effect. Overall: VUS - the combination of 1 Moderate (PS3) and 2 Supporting (PM2, PP3) criteria meets no PTEN VCEP Pathogenic/Likely Pathogenic rule, and no benign rule applies.

PS3 + PM2 + PP3 → VUS

Gene diagram · NM_000314.8 · variants mapped to exon structure

PTEN NM_000314.8

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 17 assessed

Applied · 3

Strength Supporting Moderate Strong Very strong

✓

PS3 moderate Pathogenic

Met (Moderate): Mighell 2018 saturation-mutagenesis assay gives cumulative fitness score -4.645, far below the -1.11 PS3_Moderate threshold, indicating severe loss of lipid phosphatase activity.

PTEN VCEP v3.2 PS3 rule (cspec doc 135637575): PS3_Moderate when 'Phosphatase activity ≤ -1.11 per Mighell et al. 2018, PMID: 29706350'.mmc2.xlsx Table S2 row L70R: Cum_score = -4.645, Cum_SE = 0.449, High_conf = True (Pass SE Filter), Imputed_score = NA (directly measured). Cum_score -4.645 ≤ -1.11, so the variant meets the VCEP PS3_Moderate threshold.PMID:29706350 Table 1 footnote c: 'Total < WT: less than wild-type; variants with scores less than or equal to −1.11, the lower 95th percentile (two-tailed) for synonymous variants.' Confirms score scale and threshold semantics.

PMID:29706350 ↗cspec ↗

✓

PM2 supporting Pathogenic

Met (Supporting): variant is entirely absent (AF = 0) from gnomAD v2.1, v4.1, and gnomAD-Canada.

gnomAD v2.1 exome lookup (10-89685314-T-G, GRCh37): variant absent (AF = 0)gnomAD v4.1 exome lookup (chr10-87925557-T-G, GRCh38): variant absent (AF = 0)gnomAD-Canada v1.0 (HostSeq genomes) lookup: variant absent (AF = 0)

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗cspec ↗

✓

PP3 supporting Pathogenic

Met (Supporting): REVEL score 0.985 exceeds the VCEP cutoff of 0.7, strongly predicting a deleterious missense effect.

REVEL v1.3 local lookup (source_registry key 'revel'): REVEL score 0.985 for NM_000314.8:c.209T>G (p.Leu70Arg).ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.2 (cspec doc 135637575): PP3 rule for missense variants = 'REVEL score > 0.7', default strength Pathogenic Supporting.Pejaver et al. 2022, Am J Hum Genet, PMID 36413997, Table 2: SVI-calibrated REVEL PP3_Strong threshold >= 0.965; score 0.985 exceeds it (corroborating only; VCEP strength applied).

cspec ↗spliceai ↗

Assessed · not applied

Pathogenic

PS1 Not assessed: insufficient evidence was available to determine whether p.Leu70Arg matches a known pathogenic variant at the same residue.

PS2 Not assessed: no confirmed or assumed de novo occurrence, parental testing, or family history data was documented.

PS4 Not assessed: no case-control study or proband phenotype/specificity scores were available.

PM1 Not assessed: insufficient evidence was available to evaluate whether Leu70 lies in a PM1-defined mutational hotspot.

PM5 Not assessed: insufficient evidence was available to determine whether a known pathogenic variant alters the same residue.

PM6 Not assessed: no assumed de novo occurrence or parental testing data was documented.

PP1 Not assessed: no co-segregation or meiosis data was available.

PP2 Not assessed: insufficient evidence was available to evaluate the gene's missense variation burden.

Benign

BA1 Not met: allele frequency is 0 in gnomAD, far below the >0.056% BA1 threshold.

BS1 Not met: allele frequency is 0 in gnomAD, below even the lowest 0.00043% BS1 band.

BS2 Not met: no homozygous observations exist - the variant is absent from gnomAD.

BS3 Not met: functional data show the opposite - a fitness score of -4.645 indicates severely reduced phosphatase activity, not >0 as BS3 requires.

BS4 Not assessed: no family data demonstrating lack of segregation was available.

BP1 Not assessed: insufficient evidence was available to evaluate the variant's frequency in affected individuals.

BP2 Not met: no trans or cis observations with a pathogenic PTEN variant were documented.

BP4 Not met: REVEL 0.985 is above the <0.5 BP4 threshold.

BP5 Not assessed: no cases with an alternate molecular basis for disease were documented.

N/A · 8 PVS1 · PM3 · PM4 · PP4 · PP5 · BP3 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 1785871)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.15). REVEL score = 0.985. BayesDel score = 0.595825.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PTEN, a lipid and protein phosphatase, is one of the most frequently mutated genes in cancer.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV109700563, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 6 further PMIDs triaged but not cited — see Sources & References.

Rule & framework references · cited for criterion definitions, not variant evidence

29706350 ↗ A Saturation Mutagenesis Approach to Understanding PTEN Lipid Phosphatase Activity and Genotype-Phenotype Relationships.

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 6 PMIDs not cited in assessment

17392385 ↗ American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CLINVAR

20301661 ↗ PTEN Hamartoma Tumor Syndrome. CLINVAR

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics CLINVAR

25645574 ↗ ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. CLINVAR

26389333 ↗ Genetics of Skin Cancer (PDQ®): Health Professional Version. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification crite CLINVAR