NM_014159.6:c.4264C>T is a nonsense variant in SETD2 predicted to produce a premature termination codon at p.Gln1422Ter (Q1422*).1 SETD2 loss-of-function is an established disease mechanism for autosomal dominant Luscan-Lumish syndrome (SETD2-related overgrowth syndrome), supported by multiple germline publications.2 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).3 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting PM2 at supporting strength.4 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.5 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.6 Overall classification: PVS1 (very_strong) + PM2 (supporting) = Likely Pathogenic per ACMG/AMP 2015 combination rules.7
SETD2
Final classification
VUS
SETD2 c.4264C>T · p.Gln1422Ter
SETD2
NM_014159.6:c.4264C>T is a nonsense variant in SETD2 predicted to produce a premature termination codon at p.Gln1422Ter (Q1422*).
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 supporting; combination = 1 very strong + 1 supporting, which maps to VUS.
Classification rationale
PVS1PM2
VUS
SETD2 c.4264C>T
PVS1 + PM2
→
VUS
1
pvs1_variant_assessment
2
pvs1_gene_context
7
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
✓
PVS1
very strong
Pathogenic
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.
Nonsense variant p.(Gln1422Ter) in SETD2SETD2 loss-of-function is established germline disease mechanism (Luscan-Lumish overgrowth syndrome)Variant in exon 3 of 21
✓
PM2
supporting
Pathogenic
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.
Absent from gnomAD v2.1 (exomes)Absent from gnomAD v4.1 (exomes)Absent from gnomAD-Canada v1.0 (genomes)
Assessed · not applied
Pathogenic
PS1
No previously established pathogenic variant producing the same amino acid change (Q1422*) was identified.
PS2
No de novo observation with confirmed maternity and paternity was available for this variant, so PS2 is not met.
PS3
No functional data exist for NM_014159.6:c.4264C>T (p.Q1422*).
PS4
Insufficient affected individual data to establish statistically significant enrichment compared to controls.
PM1
The variant is not located within the SET catalytic domain (residues ~1550-1700) or a statistically significant mutational hotspot as defined by cancerhotspots.org.
PM5
No comparator variant at the same residue (Q1422) with a different pathogenic amino acid change was identified.
PM6
No report of a de novo occurrence (with or without confirmed parentage) was available for this variant.
PP1
No segregation data were available to assess co-segregation of this variant with disease in affected family members.
PP3
Computational evidence for pathogenicity is not applicable for this nonsense variant in the traditional PP3 sense.
PP4
No detailed patient phenotype or family history was available to determine if the clinical presentation is highly specific for SETD2-related overgrowth syndrome.
PP5
ClinVar classification is 'Likely oncogenic' with review status 'criteria provided, single submitter' (1-star).
Benign
BA1
The variant is absent from all population databases (gnomAD v2.1, v4.1, Canada).
BS1
The variant is absent from population databases and does not meet the BS1 threshold of allele frequency >0.3%.
BS2
No evidence of this variant being observed in healthy adult individuals in a manner that would support a benign interpretation.
BS3
No functional studies demonstrating a neutral or benign effect of this variant were identified.
BS4
No evidence of non-segregation with disease was available.
BP2
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.
BP4
BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product.
BP5
No evidence of this variant being observed in a case with an alternate molecular basis for disease.
BP6
ClinVar classification is 'Likely oncogenic' with review status 'criteria provided, single submitter' (1-star).
N/A · 6
PM3 · PM4 · PP2 · BP1 · 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
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar but submission details could not be extracted. (ClinVarID = 4539793)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). BayesDel score = 0.66.
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.
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; COSV109429436, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 8 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
32674319 ↗
Loss of Function SETD2 Mutations in Poorly Differentiated Metastases from Two Hürthle Cell Carcinomas of the Thyroid.
CLINVAR
35101336 ↗
Standards for the classification of pathogenicity of somatic variants in cancer (oncogenicity): Joint recommendations of Clinical Genome Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant Interpretation for Cancer Consortium (VICC).
CLINVAR
22918138 ↗
Opportunities and challenges associated with clinical diagnostic genome sequencing: a report of the Association for Molecular Pathology.
CLINVAR
34131312 ↗
Chromosomal microarray analysis, including constitutional and neoplastic disease applications, 2021 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG).
CLINVAR
23619274 ↗
American College of Medical Genetics and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in neoplastic disorders.
CLINVAR