NM_014159.6:c.5746C>T

SETD2 · NP_054878.5:p.(Pro1916Ser) · NM_014159.6

GRCh37: chr3:47125524 G>A · GRCh38: chr3:47084034 G>A

Gene: SETD2 Transcript: NM_014159.6

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

SETD2

Transcript

NM_014159.6

Protein

NP_054878.5:p.(Pro1916Ser)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_014159.6:c.5746C>T (p.Pro1916Ser) in SETD2 is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_Supporting).

Multiple in silico tools predict a benign effect: REVEL 0.204, BayesDel -0.265772, and SpliceAI max delta 0.00 (BP4_Supporting).

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 is restricted to null variants (nonsense, frameshift, canonical splice ±1/2, initiation codon, single/multi-exon deletion). NM_014159.6:c.5746C>T is a missense substitution (p.Pro1916Ser) and does not fall into any PVS1-eligible variant bucket per PMC6185798.	pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	No known pathogenic variant at SETD2 amino acid position 1916 with a different nucleotide change exists in ClinVar. PS1 requires a different nucleotide change at the same amino acid position that has been classified as pathogenic.	clinvar
PS2	Not met	No de novo evidence is available for this variant. No publications or clinical databases report de novo occurrence of NM_014159.6:c.5746C>T.	clinvar
PS3	Not met	No well-established functional studies have been performed on this specific variant (p.Pro1916Ser) or a systematically characterized range that includes position 1916. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. In silico scores (REVEL 0.204, BayesDel -0.265772) are benign-leaning and do not constitute functional evidence for PS3.	oncokb revel bayesdel
PS4	Not met	Variant prevalence in affected individuals has not been established. This variant is absent from ClinVar and absent from gnomAD. No case-control studies demonstrating enrichment in affected individuals are available.	clinvar gnomad_v2 gnomad_v4
PS5	N/A	PS5 requires a ClinVar expert panel pathogenic classification for a variant at the same residue with a different amino acid change. This variant is absent from ClinVar, and no PM5 candidate comparators exist at position 1916.	clinvar pm5_candidates
PM1	Not met	Position 1916 is C-terminal to the SET domain of SETD2 and does not lie within a well-characterized critical functional domain. Cancerhotspots.org does not identify this residue as a statistically significant hotspot. No CSPEC/VCEP framework identifies position 1916 as a mutational hotspot.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No different pathogenic missense variant at SETD2 amino acid position 1916 has been identified in ClinVar. Automated PM5 candidate harvesting confirmed zero same-residue comparator candidates.	pm5_candidates clinvar
PM6	Not met	No de novo evidence is available for this variant. PM6 requires a de novo observation with confirmed maternity and paternity.	clinvar
PP1	Not met	No segregation data are available for this variant. PP1 requires co-segregation of the variant with disease in multiple affected family members.
PP2	Not met	PP2 requires a CSPEC/VCEP-defined low rate of benign missense variation and high rate of pathogenic missense variation for the gene. No CSPEC/VCEP framework exists for SETD2, and insufficient data are available to apply this criterion generically.
PP3	Not met	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). These do not support a deleterious effect.	revel bayesdel spliceai
PP4	Not met	No specific patient phenotype information is available for this case. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5	Not met	This variant is absent from ClinVar. PP5 requires a reputable source (≥3-star ClinVar expert panel) to have classified the variant as pathogenic.	clinvar
BA1	Not met	This variant is absent from gnomAD (v2.1, v4.1, and gnomAD-Canada). BA1 requires an allele frequency >1% in population databases.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from gnomAD. BS1 requires an allele frequency >0.3% for a dominant disorder (>0.5% for recessive) in population databases.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No homozygous or hemizygous observations of this variant in healthy individuals are available. BS2 requires observation in a healthy adult at a frequency consistent with full penetrance for recessive/dominant disease.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing exist for this variant. In silico predictions (REVEL, BayesDel) are computational and do not constitute functional studies under BS3.	revel bayesdel oncokb
BS4	Not met	No segregation data demonstrating lack of co-segregation with disease are available for this variant.
BP1	Not met	No evidence that this missense variant occurs in trans with a pathogenic SETD2 variant. BP1 requires a missense variant in a gene where truncating variants cause disease to be observed in trans with a pathogenic variant.
BP2	Not met	No observation of this variant in trans with a pathogenic SETD2 variant or in cis with a pathogenic variant in a recessive disorder. No data available.
BP3	N/A	Skipped: trivially not applicable per instruction.
BP4	Met	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 bayesdel spliceai
BP5	Not met	No alternative molecular cause for the phenotype has been identified in this case. BP5 requires a variant found in a case with an alternative molecular basis for disease.
BP6	Not met	This variant is absent from ClinVar. BP6 requires a reputable source (≥3-star ClinVar expert panel) to have classified the variant as benign or likely benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. NM_014159.6:c.5746C>T is a missense variant (p.Pro1916Ser), not synonymous.

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