NM_014159.6:c.4264C>T

SETD2 · NP_054878.5:p.(Gln1422Ter) · NM_014159.6

GRCh37: chr3:47161862 G>A · GRCh38: chr3:47120372 G>A

Gene: SETD2 Transcript: NM_014159.6

Final call

VUS

PVS1 very strong PM2 supporting

Variant details

Gene

SETD2

Transcript

NM_014159.6

Protein

NP_054878.5:p.(Gln1422Ter)

gnomAD AF

ClinVar

Likely oncogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_014159.6:c.4264C>T is a nonsense variant in SETD2 predicted to produce a premature termination codon at p.Gln1422Ter (Q1422*).

SETD2 loss-of-function is an established disease mechanism for autosomal dominant Luscan-Lumish syndrome (SETD2-related overgrowth syndrome), supported by multiple germline publications.

The variant lies in exon 3 of 21 and is predicted to trigger nonsense-mediated decay, satisfying PVS1 at very strong strength under the ClinGen SVI framework (PMC6185798).

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting PM2 at supporting strength.

No variant-specific functional data are available. The literature reviewed discusses SETD2 at the gene level or reports different SETD2 variants; none tested c.4264C>T (p.Q1422*) directly.

ClinVar records this variant as 'Likely oncogenic' by a single submitter in a somatic context; this classification does not meet the threshold for germline PP5 or BP6 application.

Overall classification: PVS1 (very_strong) + PM2 (supporting) = Likely Pathogenic per ACMG/AMP 2015 combination rules.

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	NM_014159.6:c.4264C>T is a nonsense variant predicted to introduce a premature termination codon at p.Gln1422Ter (Q1422*). SETD2 loss-of-function is an established germline disease mechanism for Luscan-Lumish syndrome (SETD2-related overgrowth syndrome; PMID:24852293, PMID:31643139). The variant lies in exon 3 of 21 (c.4264 of 7695 coding bases), well upstream of the final exon, and is predicted to trigger nonsense-mediated decay. Under the ClinGen SVI PVS1 framework (PMC6185798), this qualifies for PVS1 at very strong strength.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No previously established pathogenic variant producing the same amino acid change (Q1422*) was identified. PS1 requires that the exact same amino acid change has been established as pathogenic through a different nucleotide change.
PS2	Not met	No de novo observation with confirmed maternity and paternity was available for this variant, so PS2 is not met.
PS3	Not met	No functional data exist for NM_014159.6:c.4264C>T (p.Q1422). The one paper flagged for PS3 (PMID:32674319) describes a different SETD2 truncating variant (p.D1890fs6), not c.4264C>T. The remaining gene-level functional literature does not test this specific variant. No variant-specific or systematically characterized range includes this position.
PS4	Not met	Insufficient affected individual data to establish statistically significant enrichment compared to controls. The variant has been reported in COSMIC once in a somatic context (COSV109429436) and in ClinVar as likely oncogenic by a single submitter, but no case-control data or multiple independent proband observations are available for germline disease.
PS5	N/A	PS5 applies to variants found in trans with a pathogenic variant for recessive disorders. SETD2-related disease is autosomal dominant (Luscan-Lumish syndrome); PS5 does not apply.
PM1	Not met	The variant is not located within the SET catalytic domain (residues ~1550-1700) or a statistically significant mutational hotspot as defined by cancerhotspots.org. The p.Q1422* stop codon is N-terminal to the SET domain and truncates the protein before that region. While the truncation removes critical C-terminal domains, this mechanism is already accounted for by PVS1.
PM2	Met	The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases, indicating it is extremely rare or absent in the general population.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No comparator variant at the same residue (Q1422) with a different pathogenic amino acid change was identified. The PM5 candidate search found no same-residue candidates with expert panel or majority pathogenic classifications.
PM6	Not met	No report of a de novo occurrence (with or without confirmed parentage) was available for this variant.
PP1	Not met	No segregation data were available to assess co-segregation of this variant with disease in affected family members.
PP2	N/A	PP2 applies to missense variants in genes where missense is a common disease mechanism and benign missense variation is rare. This variant is a nonsense change, not missense.
PP3	Not met	Computational evidence for pathogenicity is not applicable for this nonsense variant in the traditional PP3 sense. PP3 is designed for missense variants where in silico tools predict deleterious effect. The deleterious mechanism of a stop-gain variant is self-evident from the variant type and is already captured by PVS1. SpliceAI predicts no splice impact (max delta 0.03). BayesDel score is 0.66, which is not strongly predictive in isolation.	spliceai
PP4	Not met	No detailed patient phenotype or family history was available to determine if the clinical presentation is highly specific for SETD2-related overgrowth syndrome.
PP5	Not met	ClinVar classification is 'Likely oncogenic' with review status 'criteria provided, single submitter' (1-star). This does not meet the 3-star expert panel threshold required for PP5 under generic ACMG/AMP. Additionally, the ClinVar entry reflects a somatic oncogenicity classification, not a germline pathogenicity assessment.	clinvar
BA1	Not met	The variant is absent from all population databases (gnomAD v2.1, v4.1, Canada). It does not meet the BA1 threshold of allele frequency >1%.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from population databases and does not meet the BS1 threshold of allele frequency >0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	No evidence of this variant being observed in healthy adult individuals in a manner that would support a benign interpretation. BS2 requires observation in a healthy adult for a fully penetrant dominant disorder; no such data are available.
BS3	Not met	No functional studies demonstrating a neutral or benign effect of this variant were identified.
BS4	Not met	No evidence of non-segregation with disease was available. BS4 requires documented lack of segregation in affected family members; no such data exist.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This variant is itself a truncating (nonsense) variant, making BP1 inapplicable.
BP2	Not met	No evidence of this variant being observed in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant. BP2 requires such observations; none exist.
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. As a nonsense variant creating a premature termination codon at position 1422, the variant has a clear and significant impact on the gene product (truncated protein or NMD). Computational tools supporting a benign interpretation do not apply. SpliceAI predicts no splice impact (max delta 0.03), but this does not offset the definitive impact of the stop-gain itself.	spliceai
BP5	Not met	No evidence of this variant being observed in a case with an alternate molecular basis for disease. BP5 requires such an observation; none is available.
BP6	Not met	ClinVar classification is 'Likely oncogenic' with review status 'criteria provided, single submitter' (1-star). This does not meet the 3-star expert panel threshold required for BP6 under generic ACMG/AMP. The ClinVar entry reflects a somatic assessment, not a germline benign classification.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This variant is a nonsense (stop-gain) substitution, not synonymous.
BP3	N/A	Skipped: BP3 applies to in-frame indels in repetitive regions; this is a substitution variant.
PM3	N/A	Skipped: PM3 applies to recessive disorders; SETD2-related disease is autosomal dominant.
PM4	N/A	Skipped: PM4 applies to in-frame deletions/insertions or stop-loss variants; this is a substitution producing a stop-gain.

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