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SETD2c.4264C>TUncertain significance
Print report
Variant interpretation report

SETD2 c.4264C>T, p.(Gln1422Ter)

NM_014159.6:c.4264C>T NP_054878.5:p.(Gln1422Ter) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About SETD2

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

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.

PM2Supporting
PM2 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.030 maximum delta

Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded. ClinVar API review status: criteria provided, single submitter.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV109429436, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 20 not met · 0 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

Met · 2

PVS1 Very strongNM_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. Details ▾Hide ▴
Evidence considered
  • Nonsense variant p.(Gln1422Ter) in SETD2
  • SETD2 loss-of-function is established germline disease mechanism (Luscan-Lumish overgrowth syndrome)
  • Variant in exon 3 of 21
  • NMD predicted
  • ClinGen SVI PVS1 framework (PMC6185798) applied
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PM2 SupportingThe 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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes)
  • Absent from gnomAD v4.1 (exomes)
  • Absent from gnomAD-Canada v1.0 (genomes)
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 20 · evaluated, threshold not reached

PS1 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. Details ▾Hide ▴
Still missing
  • No known pathogenic variant at the same codon producing the same stop codon via a different nucleotide substitution
PS2 No de novo observation with confirmed maternity and paternity was available for this variant, so PS2 is not met. Details ▾Hide ▴
Still missing
  • No de novo testing data available
PS3 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. Details ▾Hide ▴
Evidence considered
  • PMID:32674319 describes p.D1890fs6*
  • not the queried variant
  • No functional study tested c.4264C>T (p.Q1422*) directly
Still missing
  • No variant-specific functional data available
PS4 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. Details ▾Hide ▴
Evidence considered
  • COSMIC: 1 somatic observation (COSV109429436)
  • ClinVar: single submitter
  • no clinical proband details
Still missing
  • No case-control data or multiple independent proband observations
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. 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. Details ▾Hide ▴
Evidence considered
  • Cancerhotspots.org: no significant hotspot at this residue
  • p.Q1422* is upstream of the SET catalytic domain
PM5 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. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search returned 0 same-residue candidates
Still missing
  • No known pathogenic missense variant at codon 1422
PM6 No report of a de novo occurrence (with or without confirmed parentage) was available for this variant. Details ▾Hide ▴
Still missing
  • No de novo report available
PP1 No segregation data were available to assess co-segregation of this variant with disease in affected family members. Details ▾Hide ▴
Still missing
  • No family segregation data
PP3 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.03 (no splice impact)
  • BayesDel 0.66 (intermediate score)
Sources
spliceai ↗
PP4 No detailed patient phenotype or family history was available to determine if the clinical presentation is highly specific for SETD2-related overgrowth syndrome. Details ▾Hide ▴
Still missing
  • No phenotype-specific data provided for the proband
PP5 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. Details ▾Hide ▴
Evidence considered
  • ClinVar: Likely oncogenic
  • criteria provided single submitter (1-star
  • not EP)
Sources
clinvar ↗
BA1 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%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD (AF = 0)
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The variant is absent from population databases and does not meet the BS1 threshold of allele frequency >0.3%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD (AF = 0)
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 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. Details ▾Hide ▴
Still missing
  • No observation in healthy adult controls
BS3 No functional studies demonstrating a neutral or benign effect of this variant were identified. Details ▾Hide ▴
Still missing
  • No functional data showing no deleterious effect
BS4 No evidence of non-segregation with disease was available. BS4 requires documented lack of segregation in affected family members; no such data exist. Details ▾Hide ▴
Still missing
  • No segregation data
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. BP2 requires such observations; none exist. Details ▾Hide ▴
Still missing
  • No phase data with other pathogenic variants
BP4 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.03 (no splice impact)
  • But stop-gain is inherently deleterious
  • BP4 is not applicable to nonsense variants
Sources
spliceai ↗
BP5 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. Details ▾Hide ▴
Still missing
  • No alternate molecular diagnosis available
BP6 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. Details ▾Hide ▴
Evidence considered
  • ClinVar: Likely oncogenic
  • single submitter (1-star
  • not EP)
Sources
clinvar ↗
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/ASkipped: PM3 applies to recessive disorders; SETD2-related disease is autosomal dominant. Details ▾Hide ▴

No further detail was recorded.

PM4 N/ASkipped: PM4 applies to in-frame deletions/insertions or stop-loss variants; this is a substitution producing a stop-gain. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 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. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 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. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ASkipped: BP3 applies to in-frame indels in repetitive regions; this is a substitution variant. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a nonsense (stop-gain) substitution, not synonymous. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 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. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
SETD2
Transcript
NM_014159.6
Coding (HGVS c.)
NM_014159.6:c.4264C>T
Protein (HGVS p.)
NP_054878.5:p.(Gln1422Ter)
GRCh38
chr3:47120372 G>A
GRCh37
chr3:47161862 G>A
ClinVar
4539793
COSMIC
COSV109429436

Gene diagram

Every interpreted variant in SETD2, mapped onto the exon structure of NM_014159.6. Select a row to find it on the plot.

SETD2NM_014159.6
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -445 bp
0.000
SpliceAI acceptor gainat -36 bp
0.000
SpliceAI donor lossat -190 bp
0.030
SpliceAI donor gainat +170 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.010

Other predictors

REVEL
Not available
BayesDel
0.660

How the predictions were used

PP3 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.03 (no splice impact)
  • BayesDel 0.66 (intermediate score)
Sources
spliceai ↗
BP4 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.03 (no splice impact)
  • But stop-gain is inherently deleterious
  • BP4 is not applicable to nonsense variants
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a nonsense (stop-gain) substitution, not synonymous. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). BayesDel score = 0.66.

8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Mutations in SETD2 and genes affecting histone H3K36 methylation target hemispheric high-grade gliomas.
    Identified SETD2 mutations in 15% of pediatric high-grade gliomas using whole-exome sequencing, establishing SETD2 as a tumor suppressor gene in this context. Discusses gene-level mutational patterns and H3K36 trimethylation loss. NM_014159.6:c.4264C>T was not identified in this paper.
    Does not name this variant
    PMID 23417712 ↗
  • Identification of functional cooperative mutations of SETD2 in human acute leukemia.
    Identified biallelic SETD2 mutations (including a nonsense mutation) as cooperative events in MLL-rearranged acute leukemia using whole-genome sequencing of discordant monozygotic twins. NM_014159.6:c.4264C>T was not identified in this paper.
    Does not name this variant
    PMID 24509477 ↗
  • SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair.
    Demonstrated that SETD2 loss-of-function promotes branched evolution in clear cell renal carcinoma through replication stress and impaired DNA repair. Reports SETD2 mutations in 4-8% of ccRCC. NM_014159.6:c.4264C>T was not identified in this paper.
    Does not name this variant
    PMID 25728682 ↗
  • Loss of Function SETD2 Mutations in Poorly Differentiated Metastases from Two Hürthle Cell Carcinomas of the Thyroid.
    Pecce V et al. · 2020
    Reports SETD2 p.D1890fs6* frameshift mutation in two Hürthle cell carcinoma metastases. Functional assays demonstrated loss of H3K36me3 and truncated protein lacking WW and SRI domains. NM_014159.6:c.4264C>T (p.Q1422*) was not identified in this paper.
    Does not name this variant
    PMID 32674319 ↗
  • 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).
    Horak P et al. · 2022
    Joint consensus recommendations for somatic variant oncogenicity classification by ClinGen, CGC, and VICC. Provides standards for classifying somatic variants but does not discuss any specific SETD2 variant. NM_014159.6:c.4264C>T was not identified in this paper.
    Does not name this variant
    PMID 35101336 ↗
  • Opportunities and challenges associated with clinical diagnostic genome sequencing: a report of the Association for Molecular Pathology.
    Schrijver I et al. · 2012
    Association for Molecular Pathology report on opportunities and challenges of clinical diagnostic genome sequencing. Reviews NGS technologies, applications in inherited conditions and cancer, and ethical considerations. Does not mention SETD2 or any specific variant. NM_014159.6:c.4264C>T was not identified in this paper.
    Does not name this variant
    PMID 22918138 ↗
  • Chromosomal microarray analysis, including constitutional and neoplastic disease applications, 2021 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG).
    Shao L et al. · 2021
    ACMG technical standard for chromosomal microarray analysis in constitutional and neoplastic disease applications. Provides laboratory standards for CMA validation and interpretation. Does not mention SETD2 or any specific variant. NM_014159.6:c.4264C>T was not identified in this paper.
    Does not name this variant
    PMID 34131312 ↗
  • American College of Medical Genetics and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in neoplastic disorders.
    Cooley LD et al. · 2013
    ACMG technical standards and guidelines for microarray analysis in neoplastic disorders (2013). Provides cytogenomic laboratory standards. NM_014159.6:c.4264C>T was not identified. Abstract review only; full text not retrieved because the paper is a technical guideline unrelated to SETD2.
    Does not name this variant
    PMID 23619274 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.030 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

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

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV109429436, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.