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SETD2
Final classification
Likely Pathogenic
PVS1PM2BP4
SETD2
c.4260del
p.Glu1420AspfsTer12
frameshift · exon 3
Gene context NCBI Gene ↗ OncoKB ↗

SETD2 is a tumor suppressor gene that encodes a histone methyltransferase which adds trimethyl marks to lysine-36 of histone H3 (H3K36me3), a modification that promotes active chromatin and helps regulate gene expression during transcription. It was originally identified as a huntingtin-interacting protein, linking it to Huntington's disease. SETD2 activity also supports DNA mismatch repair, so its loss leads to genetic instability and can drive cancer; SETD2 inactivation is especially common in kidney (renal cell) cancers, where it contributes to defective p53-mediated DNA damage repair.

This variant

SETD2 is a tumor suppressor whose loss drives genomic instability and cancer, with germline loss-of-function variants causing overgrowth/Sotos-like syndrome. This frameshift, predicted to eliminate SETD2 function via nonsense-mediated decay, fits that established loss-of-function mechanism, supporting its Likely Pathogenic classification.

Transcript
NM_014159.6
HGVS · transcript:coding
NM_014159.6:c.4260del
GRCh38
chr3:47120375 GC>G
GRCh37
chr3:47161865 GC>G
Basis PVS1 (Very Strong) plus PM2 (Supporting) gives Likely Pathogenic under generic ACMG/AMP 2015 combination rules; the single supporting BP4 does not reach a benign threshold. ▾
PVS1 (Very Strong) plus PM2 (Supporting) gives Likely Pathogenic under generic ACMG/AMP 2015 combination rules; the single supporting BP4 does not reach a benign threshold.
Classification rationale
PVS1PM2 BP4 Likely Pathogenic
SETD2 c.4260del frameshift · exon 3

PVS1 (Very Strong): frameshift p.(Glu1420AspfsTer12) introduces a premature stop 12 residues downstream, predicted to trigger nonsense-mediated decay. PM2 (Supporting): the deletion is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BP4 (Supporting): SpliceAI max delta 0.014 indicates no splice impact, but a single benign-supporting criterion does not override the pathogenic combination. PVS1 (Very Strong) + PM2 (Supporting) = Likely Pathogenic under generic ACMG/AMP 2015 rules.

PVS1 + PM2 + BP4 → Likely Pathogenic
Gene diagram · NM_014159.6 · variants mapped to exon structure
SETD2 NM_014159.6
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 17 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 · 3
Strength Supporting Moderate Strong Very strong
✓
PVS1 very strong Pathogenic
Met (Very Strong): the single-nucleotide deletion creates frameshift p.(Glu1420AspfsTer12), with a premature stop 12 residues downstream predicted to trigger nonsense-mediated decay.
case_summary.json normalization: NM_014159.6:c.4260del produces NP_054878.5:p.(Glu1420AspfsTer12), a frameshift consequence (consequence_class=frameshift, variant_bucket=frameshift).pvs1_variant_assessment.json: framework_source is ClinGen SVI PVS1 recommendations (PMC6185798); apply_generic_pvs1_framework=true; suggested_default_strength=PVS1; rationale confirms frameshift variants are evaluated with the generic PVS1 framework once germline LoF is established for the gene.pvs1_gene_context.json: germline_disease_context_found=true; lof_mechanism_supported=true; pvs1_gene_gate=eligible; mechanism_rationale states targeted germline literature review identified disease-focused publications supporting SETD2 loss of function as a germline disease mechanism (SETD2-related overgrowth condition/Sotos-like syndrome, citing PMID 24852293 and PMID 31643139 among supporting_sources), so generic PVS1 framework assessment is eligible.
pvs1_generic_framework ↗gnomad_v2 ↗gnomad_v4 ↗
✓
PM2 supporting Pathogenic
Met (Supporting): the deletion is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
The exact normalized deletion was queried in gnomAD v2.1 (GRCh37), gnomAD v4.1 (GRCh38), and gnomAD-Canada v1.0 (GRCh38); each source reported the variant as absent.
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
✓
BP4 supporting Benign
Met (Supporting): SpliceAI max delta 0.014 is well below the ~0.2 threshold for a splice-altering effect.
case_summary.compact_evidence.spliceai.evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).' with scores DS_AG=0.0, DS_AL=0.0, DS_DG=0.014, DS_DL=0.001, DP values all indicating distant/low-confidence positions, max_delta=0.014.SpliceAI delta score of 0.014 falls well below the ~0.2 threshold band associated with likely splice-altering variants described in the original SpliceAI publication (Jaganathan et al. 2019, Cell, PMID:30661751), supporting a benign/no-impact splicing prediction at supporting strength.
spliceai ↗
Assessed · not applied · 5 not met · 12 not assessed
Pathogenic
PS2 Not assessed: no parental testing or confirmed de novo occurrence was available.
PS3 Not assessed: no validated functional assay performed on this exact variant was available.
PS4 Not assessed: no case-control or variant-enrichment data were identified.
PM3 Not assessed: no proband carrying a second pathogenic SETD2 variant in trans was observed.
PM6 Not assessed: no de novo occurrence without confirmed parentage was reported.
PP1 Not assessed: no family pedigree or segregation data were provided.
PP3 Not met: SpliceAI max delta 0.014 is far below thresholds supporting a deleterious splice effect.
PP4 Not assessed: no proband phenotype or diagnosis information was available.
PP5 Not met: the variant is absent from ClinVar, so no expert-panel pathogenic assertion exists.
Benign
BA1 Not met: the variant is absent from gnomAD, providing no allele frequency that could satisfy BA1.
BS1 Not met: the variant is absent from gnomAD, with no frequency exceeding a benign-population threshold.
BS2 Not assessed: absence from population sources provides no adult or homozygous observations.
BS3 Not assessed: no functional assay data for this exact variant were available.
BS4 Not assessed: no non-segregation observations, unaffected carriers, or affected non-carriers were available.
BP2 Not assessed: no cis/trans co-occurrence or inheritance data were available.
BP5 Not assessed: no individual-level phenotype or alternative causal diagnosis was provided.
BP6 Not met: the variant is absent from ClinVar, so no expert-panel benign assertion exists.
N/A · 8 PS1 · PM1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
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 screenshot
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
SpliceAI ↗
Functional / OncoKB screenshot
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 screenshot
COSMIC
Cancer hotspots screenshot
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