Starting

Initialising…

SETD2

Final classification

Likely Pathogenic

SETD2 c.850del · p.Ser284ProfsTer17

SETD2

Gene

SETD2

Transcript

NM_014159.6

HGVS · transcript:coding

NM_014159.6:c.850del

Consequence

N/A

GRCh38

chr3:47123785 GA>G

GRCh37

chr3:47165275 GA>G

Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic. ▾

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.

Classification rationale

PVS1PM2 Likely Pathogenic

SETD2 c.850del

NM_014159.6:c.850del (p.Ser284ProfsTer17) is a frameshift null variant in SETD2, a gene where germline loss of function is an established mechanism for autosomal dominant overgrowth syndrome (Sotos-like).¹ This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (allele frequency 0.00 across all populations).² PVS1 (Very Strong) and PM2 (Moderate) are met. Under generic ACMG/AMP 2015 final combination rules (PMID:25741868), one Very Strong criterion plus one Moderate criterion supports a classification of Likely Pathogenic.³

PVS1 + PM2 → Likely Pathogenic

1 pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment

2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

3 generic_acmg_combination_rules

Gene diagram · NM_014159.6 · variants mapped to exon structure

SETD2 NM_014159.6

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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