Classification rationale

PVS1PM2 Likely Pathogenic

PTEN c.722_723dup frameshift · exon 7

PVS1 very strong: the p.E242Lfs*15 frameshift is 5' of the PTEN VCEP p.D375 NMD threshold and is predicted to undergo nonsense-mediated decay. PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the PTEN VCEP population-frequency rule.

PVS1 + PM2 → Likely Pathogenic

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

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

PTEN NM_000314.8

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 14 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

PVS1 very strong Pathogenic

Met: the p.E242Lfs*15 frameshift is 5' of the PTEN VCEP p.D375 NMD threshold, so the decision tree assigns full-strength PVS1.

The case normalization identifies NM_000314.8:c.722_723dup as a frameshift producing NP_000305.3:p.(Glu242LeufsTer15), also represented as p.(E242Lfs*15).The PTEN VCEP decision tree states that a nonsense or frameshift variant with a stop codon or disruption at or 5' to p.D375 (c.1121), in biologically relevant transcript NM_000314.8 and predicted to undergo NMD, receives PVS1.The PTEN VCEP specification explicitly directs reviewers to use the PTEN PVS1 decision tree for PVS1 strength assignment.

cspec ↗

PM2 supporting Pathogenic

Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the PTEN PM2 absence criterion below 0.00001 allele frequency.

The governing ClinGen PTEN Expert Panel Version 3.2 defines PM2 supporting as absent from gnomAD or another large sequenced population, with allele frequency <0.00001 (0.001%); if multiple alleles occur in a subpopulation, that subpopulation frequency must be <0.00002 (0.002%).The variant is reported absent from gnomAD v2.1 and gnomAD v4.1.The variant is also reported absent from GNOMAD_V2_1_NON_CANCER and GNOMAD_V3_1_NON_CANCER, including the specified non-cancer cohort views.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 4 not met · 10 not assessed

Pathogenic

PS2 Not assessed: no documented proband-level parental testing, confirmed maternity and paternity, or absence of family history for c.722_723dup.

PS3 Not assessed: the governing PTEN assay table covers missense variants and contains no entry for this frameshift, c.722_723dup / p.E242Lfs*15.

PS4 Not assessed: no variant-specific specificity score or qualifying case-control odds ratio, p value, and confidence interval are available for c.722_723dup.

PM1 Not met: residue 242 is outside PTEN VCEP critical motifs 90-94, 123-130, and 166-168, and no E242 hotspot was identified.

PM4 Not met: p.E242Lfs*15 is a frameshift with premature termination, whereas the PTEN PM4 rule requires an in-frame length change or stop-loss extension.

PM6 Not assessed: no documented presumed de novo proband observation, parental testing status, or family-history assessment for c.722_723dup.

PP1 Not assessed: zero informative meioses or exact-variant affected-relative segregation data are documented, below the PTEN VCEP minimum of 3 meioses.

Benign

BA1 Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the PTEN BA1 threshold of 0.00056 allele frequency.

BS1 Not met: the variant is absent from gnomAD v2.1 and v4.1, below both PTEN BS1 intervals beginning at 0.0000043 allele frequency.

BS2 Not assessed: no homozygous observation in a healthy or PHTS-unaffected individual is available to satisfy the PTEN BS2 rule.

BS3 Not assessed: no variant-specific benign functional result was found for the frameshift c.722_723dup / p.E242Lfs*15 in the governing PTEN assay material.

BS4 Not assessed: no tested affected relatives or family-level non-segregation observations are documented for c.722_723dup.

BP2 Not assessed: no paired pathogenic PTEN variant or documented cis/trans/phase observation is available to satisfy the BP2 rule.

BP5 Not assessed: no two qualifying cases with a highly penetrant alternate diagnosis and non-overlapping PTEN histories are documented.

N/A · 12 PS1 · PM3 · PM5 · PP2 · PP3 · PP4 · PP5 · BP1 · BP3 · BP4 · BP6 · BP7

Research & evidence

Population frequency · supports pathogenic

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 Pathogenic (2 clinical laboratories). (ClinVarID = 811414)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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; COSV64290304, n = 9 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 8 PMIDs not cited in assessment

11237521 ↗ PTEN: life as a tumor suppressor. ONCOKB

17218262 ↗ Essential role for nuclear PTEN in maintaining chromosomal integrity. ONCOKB

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

9467011 ↗ Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. CLINVAR

21194675 ↗ A clinical scoring system for selection of patients for PTEN mutation testing is proposed on the basis of a prospective study of 3042 probands. CLINVAR

23788249 ↗ ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. CLINVAR

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

26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Versi CLINVAR

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