Classification rationale

PM2 BP4 VUS

SETD2 c.5746C>T

NM_014159.6:c.5746C>T (p.Pro1916Ser) in SETD2 is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_Supporting).¹ Multiple in silico tools predict a benign effect: REVEL 0.204, BayesDel -0.265772, and SpliceAI max delta 0.00 (BP4_Supporting).² One supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) result in conflicting evidence. Under generic ACMG/AMP 2015 classification rules, this yields a Variant of Uncertain Significance (VUS).³

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 revelbayesdelspliceai ↗

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 applied · 20 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

NM_014159.6:c.5746C>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, meeting the PM2 threshold of <0.1% population frequency under the generic ACMG/AMP framework.

Absent from gnomAD v2.1 (exomes). Absent from gnomAD v4.1 (exomes/genomes). Absent from gnomAD-Canada v1.0.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Multiple lines of computational evidence suggest no impact on the gene product: REVEL score 0.204 (below 0.5 threshold), BayesDel score -0.265772 (negative, benign-leaning), and SpliceAI max delta score 0.00 (no predicted splice impact). Under generic ACMG/AMP, BP4 applies when multiple in silico tools predict a benign effect.

REVEL: 0.204 (benign-leaning). BayesDel: -0.265772 (benign-leaning). SpliceAI: max delta 0.00 (no splice effect).

spliceai ↗

Assessed · not applied

Pathogenic

PS2 No de novo evidence is available for this variant.

PS3 No well-established functional studies have been performed on this specific variant (p.Pro1916Ser) or a systematically characterized range that includes position 1916.

PS4 Variant prevalence in affected individuals has not been established.

PM1 Position 1916 is C-terminal to the SET domain of SETD2 and does not lie within a well-characterized critical functional domain.

PM5 No different pathogenic missense variant at SETD2 amino acid position 1916 has been identified in ClinVar.

PM6 No de novo evidence is available for this variant.

PP1 No segregation data are available for this variant.

PP2 PP2 requires a CSPEC/VCEP-defined low rate of benign missense variation and high rate of pathogenic missense variation for the gene.

PP3 Multiple in silico predictors suggest a benign effect: REVEL score 0.204 (below the 0.5 pathogenic threshold), BayesDel score -0.265772 (negative, benign-leaning), and SpliceAI max delta score 0.00 (no predicted splice impact).

PP4 No specific patient phenotype information is available for this case.

PP5 This variant is absent from ClinVar.

Benign

BA1 This variant is absent from gnomAD (v2.1, v4.1, and gnomAD-Canada).

BS1 This variant is absent from gnomAD.

BS2 No homozygous or hemizygous observations of this variant in healthy individuals are available.

BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing exist for this variant.

BS4 No segregation data demonstrating lack of co-segregation with disease are available for this variant.

BP1 No evidence that this missense variant occurs in trans with a pathogenic SETD2 variant.

BP2 No observation of this variant in trans with a pathogenic SETD2 variant or in cis with a pathogenic variant in a recessive disorder.

BP5 No alternative molecular cause for the phenotype has been identified in this case.

BP6 This variant is absent from ClinVar.

N/A · 4 PVS1 · PS1 · BP3 · 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 = 0.00). REVEL score = 0.204. BayesDel score = -0.265772.

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. SETD2, an H3K36 trimethylase, is altered in a variety of cancer types.

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; COSV57435928, n = 4 times).

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