NM_014159.6:c.7572dup

SETD2 · NP_054878.5:p.(Lys2525Ter) · NM_014159.6

GRCh37: chr3:47058705 T>TA · GRCh38: chr3:47017215 T>TA

Gene: SETD2 Transcript: NM_014159.6

Final call

VUS

PVS1 moderate PM2 moderate

Variant details

Gene

SETD2

Transcript

NM_014159.6

Protein

NP_054878.5:p.(Lys2525Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_014159.6:c.7572dup (p.Lys2525Ter) in SETD2 is a null variant in a gene for which loss of function is an established germline disease mechanism (SETD2 overgrowth syndrome), applied at PVS1_Moderate after downgrade for location in the last exon with predicted NMD escape and truncation of a non-critical C-terminal region.

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, and absent from ClinVar, satisfying PM2_Moderate for a rare variant at extremely low population frequency.

No additional pathogenic, benign, or functional criteria are met. The three somatic-cancer publications reviewed (PMID:23417712, PMID:24509477, PMID:25728682) discuss SETD2 at the gene level but do not mention or characterize this specific variant.

Overall classification: VUS (Variant of Uncertain Significance). Two moderate pathogenic criteria (PVS1_Moderate, PM2_Moderate) fall short of the Likely Pathogenic threshold under the ACMG/AMP 2015 combination rules, which require three moderate criteria or one strong plus one moderate for Likely Pathogenic. No benign criteria are met. The evidence is insufficient to classify this variant as either likely pathogenic or likely benign.

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	Met	This duplication (NM_014159.6:c.7572dup) creates a premature termination codon at p.Lys2525Ter in SETD2, a gene for which loss of function is an established germline disease mechanism (SETD2 overgrowth syndrome; PMID:24852293). However, the variant resides in exon 21 of 21 (the last exon) and is predicted to escape nonsense-mediated decay, producing a truncated protein lacking only the C-terminal ~40 amino acids of 2,565 total residues. The removed region is not a well-characterized functional domain. Per PMC6185798, this warrants downgrade from full PVS1 to PVS1_Moderate.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No pathogenic variant at the same amino acid residue (p.Lys2525) has been reported in ClinVar for comparison.	clinvar
PS2	Not met	No de novo observation has been reported for this variant; absence of parental data precludes PS2 application.
PS3	Not met	No variant-specific functional data exists for NM_014159.6:c.7572dup. The three publications reviewed (PMID:23417712, PMID:24509477, PMID:25728682) discuss SETD2 at gene level in somatic cancer contexts but do not mention or functionally characterize c.7572dup or p.Lys2525Ter. OncoKB curation of this variant as Likely Oncogenic is based on gene-level loss-of-function inference, not direct experimental evidence for this variant.	oncokb
PS4	Not met	This variant is absent from ClinVar and gnomAD population databases. No case-control data demonstrating enrichment in affected individuals is available.	clinvar gnomad_v2 gnomad_v4
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion. No well-established in vitro/in vivo functional study with replication is available for this variant.
PM1	Not met	The variant truncates the C-terminal ~40 amino acids of SETD2. This region is not a statistically significant mutational hotspot (cancerhotspots.org negative) and does not reside within the annotated SET catalytic domain (residues ~1530-1700) or WW domain (~2350-2385). Insufficient evidence for domain-level PM1.
PM2	Met	This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, and absent from ClinVar, satisfying PM2 for a rare variant at extremely low population frequency.	gnomad_v2 gnomad_v4 gnomad_canada clinvar
PM3	N/A	No data for a recessive disorder trans observation; SETD2 overgrowth syndrome is autosomal dominant.
PM4	N/A	This duplication creates a frameshift and premature termination, not an in-frame insertion/deletion or stop-loss variant. Protein truncation is assessed under PVS1.
PM5	Not met	No pathogenic missense variant at the same residue (p.Lys2525) was identified in ClinVar as a comparator. The automated PM5 candidate search returned no candidates.	pm5_candidates clinvar
PM6	Not met	No de novo observation has been reported for this variant; assumed de novo not applicable without at least one report.
PP1	Not met	No segregation data are available for this variant.
PP2	N/A	PP2 applies specifically to missense variants in genes with a low rate of benign missense variation. This is a truncating (nonsense) variant.
PP3	Not met	This is a truncating variant whose primary effect is premature protein termination, already accounted for under PVS1. SpliceAI scores are borderline (max delta 0.38, below the 0.5 threshold for confident splice impact) and do not independently support a deleterious splicing mechanism. REVEL and BayesDel are unavailable for non-SNV variants. PP3 is not stacked with PVS1 for the same molecular effect.	spliceai
PP4	Not met	No patient phenotype or family history is available for assessment against the disease-specific presentation of SETD2 overgrowth syndrome.
PP5	Not met	This variant is absent from ClinVar. No reputable source has independently reported it as pathogenic.	clinvar
BA1	Not met	The variant is absent from all population databases, with an allele frequency far below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from population databases; allele frequency does not exceed the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	The variant has not been observed in any healthy adult individual; absent from gnomAD.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate a benign effect for this variant. No functional data exist for NM_014159.6:c.7572dup.
BS4	Not met	No family segregation data are available to demonstrate lack of cosegregation with disease.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. This is a truncating variant and does not qualify for BP1 consideration.
BP2	Not met	No co-occurrence data are available; the variant has not been observed in trans with a pathogenic SETD2 variant or in any individual.
BP3	N/A	BP3 applies to in-frame deletions or insertions in repetitive regions. This duplication results in a frameshift and premature termination, not an in-frame change in a repetitive region.
BP4	Not met	This variant creates a premature termination codon, which is predicted to alter the protein product. Multiple lines of computational evidence do not suggest a benign effect.	spliceai
BP5	Not met	No data on an alternate molecular basis for disease in a case harboring this variant are available.
BP6	Not met	This variant is absent from ClinVar. No reputable source has reported it as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This is a duplication leading to a frameshift and premature termination, not a synonymous variant.

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