Classification rationale

PVS1PM2 Likely Pathogenic

SETD2 c.6631G>T nonsense · exon 15

Likely Pathogenic: the premature stop in exon 15 of 19 is expected to undergo nonsense-mediated decay, supporting PVS1 at very strong strength. Likely Pathogenic: absence from gnomAD v2.1 and v4.1 supports PM2 at supporting strength.

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_014159.6 · variants mapped to exon structure

SETD2 NM_014159.6

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

PVS1 very strong Pathogenic

Met at very strong: c.6631G>T creates p.(Gly2211Ter) in exon 15 of 19, with four downstream exons and expected nonsense-mediated decay.

The case-specific assessment identifies NM_014159.6:c.6631G>T as a nonsense variant causing NP_054878.5:p.(Gly2211Ter).VariantValidator places the variant in exon 15, while the transcript structure contains four downstream exons; the predicted stop is 354 amino acids before the 2565-amino-acid reference protein terminus.The gene-level context supports SETD2 loss of function as a germline disease mechanism and marks the PVS1 gene gate eligible.

pvs1_generic_framework ↗

PM2 supporting Pathogenic

Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, including the available non-cancer subset checks.

gnomAD v2.1 reports the variant as absent.gnomAD v4.1 reports the variant as absent.The case data additionally report absence from GNOMAD_V2_1_NON_CANCER exomes and GNOMAD_V3_1_NON_CANCER genomes; no disease-specific population threshold requiring a different source was available because no VCEP specification was found.

gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 4 not met · 12 not assessed

Pathogenic

PS2 Not assessed: no proband-level parental testing, maternity or paternity confirmation, phenotype, or de novo observation is documented for this variant.

PS3 Not assessed: no reviewed study tested p.Gly2211Ter in a controlled functional assay, and gene-level effects of other SETD2 truncations cannot establish PS3.

PS4 Not assessed: no exact-variant affected-case/control enrichment or case-count evidence was available.

PM3 Not assessed: no affected proband, second pathogenic variant, parental testing, or phase observation is available to establish the required in-trans evidence.

PM6 Not assessed: no affected individual with an assumed de novo variant and unconfirmed parental relationships is documented for NM_014159.6:c.6631G>T.

PP1 Not assessed: zero informative meioses or affected and unaffected relatives with both phenotype and variant genotype are reported for cosegregation.

PP4 Not assessed: no patient phenotype or disease-specific clinical feature match was provided for this variant.

PP5 Not met: ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic assertion for c.6631G>T.

Benign

BA1 Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the generic BA1 frequency threshold of >5%.

BS1 Not met: the variant is absent from gnomAD v2.1 and v4.1, with no observed frequency greater than expected for disease.

BS2 Not assessed: no unaffected homozygote or multiple unaffected carriers are reported in the available population data.

BS3 Not assessed: no reviewed study tested p.Gly2211Ter and showed preserved SETD2 function in a validated assay with appropriate controls.

BS4 Not assessed: no informative unaffected relatives with reliable phenotype evaluation and confirmed absence of the variant are documented.

BP2 Not assessed: no second pathogenic variant or parental phase data establishes the cis/trans configuration required for BP2.

BP5 Not assessed: no patient-level alternative molecular diagnosis was available to support BP5.

BP6 Not met: ClinVar has no exact-variant expert-panel Benign or Likely benign assertion for c.6631G>T.

N/A · 10 PS1 · PM1 · PM4 · PM5 · PP2 · PP3 · BP1 · BP3 · BP4 · 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 is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

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 not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 3 PMIDs not cited in assessment

23417712 ↗ Mutations in SETD2 and genes affecting histone H3K36 methylation target hemispheric high-grade gliomas. ONCOKB

24509477 ↗ Identification of functional cooperative mutations of SETD2 in human acute leukemia. ONCOKB

25728682 ↗ SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair. ONCOKB

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