Classification rationale

PM2 VUS

PTEN c.758_760dup in_frame_indel_unknown · exon 7

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1, meeting the PTEN population-frequency threshold.

PM2 → VUS

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 · 1 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 · 1

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, satisfying the PTEN PM2 absence threshold of <0.00001.

ClinGen PTEN VCEP v3.2 specifies PM2 supporting for absence or allele frequency <0.00001 (0.001%) in gnomAD or another large sequenced population; when multiple alleles are present in a subpopulation, that subpopulation frequency must be <0.00002 (0.002%).The variant is absent from gnomAD v2.1 and v4.1, as well as gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer, so the PTEN PM2 absence criterion is met at supporting strength.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

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

Pathogenic

PS2 Not assessed: no documented proband phenotype, parental testing, maternity/paternity confirmation, or family-history information establishes a proven de novo occurrence.

PS3 Not assessed: the governing assay contains no c.758_760dup, p.Ile253dup, or p.I253dup entry, and the variant is an in-frame duplication rather than a tested missense substitution.

PS4 Not assessed: no case-control enrichment, proband phenotype, family history, or PTEN phenotype-specificity score was reported for this variant.

PM1 Not met: residue 253 lies outside PTEN catalytic motifs 90–94, 123–130, and 166–168, and no hotspot was identified.

PM4 Not met: p.(Ile253dup) adds one residue at 253, outside PTEN catalytic motifs 90-94, 123-130, and 166-168, and does not cause protein extension.

PM6 Not assessed: no documented assumed de novo observation, proband disease phenotype, family-history status, or count of independent de novo occurrences supports PM6.

PP1 Not assessed: no affected relatives, co-segregation results, or meioses are documented to meet the PTEN VCEP minimum of 3 meioses.

Benign

BA1 Not met: the variant is absent from gnomAD v2.1 and v4.1, so its frequency does not exceed the PTEN BA1 threshold of 0.00056.

BS1 Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than having a PTEN BS1-range frequency of 0.0000043 to 0.00056.

BS2 Not assessed: gnomAD reports no variant observation and supplies no homozygote count or healthy-individual genotype evidence for the PTEN BS2 rule.

BS3 Not assessed: the governing assay has no c.758_760dup, p.Ile253dup, or p.I253dup result, so no benign functional value is available for this in-frame duplication.

BS4 Not assessed: no affected-family testing or non-segregation observations are documented for one family or for two or more families.

BP2 Not assessed: no documented cis/trans phase observation with a pathogenic or likely pathogenic PTEN variant is available.

BP5 Not assessed: no qualifying alternate molecular diagnosis in at least two cases or non-overlapping personal and family history was reported.

N/A · 13 PVS1 · PS1 · PM3 · PM5 · PP2 · PP3 · PP4 · PP5 · BP1 · BP3 · BP4 · 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 is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

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 not previously been reported in somatic cancers (COSMIC).

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

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