Classification rationale

PM2PM6 VUS

PTEN c.30_32del in_frame_indel_unknown · exon 1

PM2 (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, below the 0.001% population frequency threshold. PM6 (Moderate): one ClinVar clinical-laboratory record reports presumed de novo occurrence with a PTEN-consistent phenotype; maternity and paternity are unconfirmed, and possible germline mosaicism is flagged for human review. VUS: PM6 (Moderate) plus PM2 (Supporting) matches no established Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination rule.

PM2 + PM6 → VUS

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

PTEN NM_000314.8

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 16 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

Met (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, below the 0.001% population frequency threshold.

ClinGen PTEN Expert Panel specifications version 3.2 define PM2 at Supporting strength for absence or allele frequency <0.00001 (0.001%) in gnomAD or another large sequenced population; if multiple alleles occur within a subpopulation, that subpopulation frequency must be <0.00002 (0.002%).The exact variant is reported as absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.Absence in all three reported population resources is below the specified PM2 frequency thresholds.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

PM6 moderate review Pathogenic

Met (Moderate): one ClinVar clinical-laboratory record reports presumed de novo occurrence with a PTEN-consistent phenotype, though maternity and paternity are unconfirmed. Flagged for human review: the record is a secondary submission that mentions possible germline mosaicism.

The PTEN Expert Panel specification defines PM6 Moderate as assumed de novo without confirmation of paternity and maternity in a proband with the disease and no family history.The exact-match ClinVar submission reports the variant as de novo or due to germline mosaicism in one individual with epilepsy, developmental delay with regression, and macrocephaly; the available record does not provide confirmed parental testing.Only one presumed de novo observation is available, so the PTEN-specific thresholds for PM6 Strong or PM6 Very Strong are not met.

cspec ↗clinvar ↗

Assessed · not applied · 5 not met · 11 not assessed

Pathogenic

PVS1 Not met: p.(Ser10del) is an in-frame single-codon deletion with no premature stop codon, so no nonsense-mediated decay is predicted.

PS2 Not assessed: confirmed maternity and paternity were not documented, which the PTEN PS2 rule requires for de novo evidence.

PS3 Not assessed: no variant-specific result for p.(Ser10del) exists in the Mighell 2018 assay (PS3 requires phosphatase activity <= -1.11).

PS4 Not assessed: neither a case-control result (odds ratio >2, p<0.05) nor proband phenotype data reaching the specificity score of 1 was available.

PM1 Not met: residue 10 lies outside the PTEN catalytic motifs (WPD loop 90-94, P-loop 123-130, TI-loop 166-168).

PM4 Not met: PM4 requires an in-frame indel affecting a catalytic motif; Ser10 is outside motifs 90-94, 123-130, and 166-168.

PP1 Not assessed: no family co-segregation data was available (supporting strength requires at least 3 informative meioses).

PP3 Not assessed: SpliceAI predicts no splice impact (max delta 0.037), but the required concordant VarSeak prediction is unavailable.

Benign

BA1 Not met: the variant is absent from gnomAD, well below the 0.056% filtering allele frequency required for BA1.

BS1 Not met: the variant is absent from gnomAD, with no observed frequency in the BS1 range (0.00043%-0.056%).

BS2 Not assessed: no homozygous observation in a healthy individual was available to support BS2.

BS3 Not assessed: no functional assay result for p.(Ser10del) was available (BS3 would require phosphatase activity >0 in Mighell 2018).

BS4 Not assessed: no affected relatives lacking the variant were documented, so lack of segregation could not be established.

BP2 Not assessed: no phase, cis, or trans observations were available to establish BP2.

BP4 Not assessed: SpliceAI predicts no splice impact (max delta 0.037), but the required concordant VarSeak result is unavailable.

BP5 Not assessed: no evidence of two affected cases with a separate highly penetrant molecular diagnosis was available.

N/A · 10 PS1 · PM3 · PM5 · PP2 · PP4 · PP5 · BP1 · 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) and as Uncertain Significance by Clingen PTEN Variant Curation Expert Panel, Clingen (expert panel). (ClinVarID = 428224)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

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; COSV64296695, 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. 5 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 · 5 PMIDs not cited in assessment

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

20301661 ↗ PTEN Hamartoma Tumor Syndrome. CLINVAR

25190698 ↗ Genetic/familial high-risk assessment: breast and ovarian, version 1.2014. CLINVAR

25356965 ↗ ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. CLINVAR

27854360 ↗ Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. CLINVAR