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SETD2c.7572dupUncertain significance
Print report
Variant interpretation report

SETD2 c.7572dup, p.(Lys2525Ter)

NM_014159.6:c.7572dup NP_054878.5:p.(Lys2525Ter) 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
PVS1Moderate
PVS1 · moderate

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.

PM2Moderate
PM2 · moderate

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.

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 moderate, PM2 moderate; combination = 2 moderate, 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
0.380 maximum delta

Recorded SpliceAI maximum delta score: 0.380. 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.

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
3 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV57443657, n = 3 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.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.

Met · 2

PVS1 ModerateThis 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. Details ▾Hide ▴
Evidence considered
  • SETD2 germline loss-of-function mechanism established (PMID:24852293
  • PMID:31643139)
  • Variant creates premature stop codon p.Lys2525Ter in last exon (21/21)
  • Generic PVS1 framework applied per PMC6185798 indicating downgrade for NMD escape and non-critical C-terminal truncation
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
PM2 ModerateThis 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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes)
  • Absent from gnomAD v4.1 (exomes)
  • Absent from gnomAD-Canada v1.0 (genomes)
  • Absent from ClinVar
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗clinvar ↗

Not met · 20 · evaluated, threshold not reached

PS1 No pathogenic variant at the same amino acid residue (p.Lys2525) has been reported in ClinVar for comparison. Details ▾Hide ▴
Evidence considered
  • ClinVar contains no entries for this variant or for any pathogenic comparator at the same residue
Sources
clinvar ↗
PS2 No de novo observation has been reported for this variant; absence of parental data precludes PS2 application. Details ▾Hide ▴
Evidence considered
  • No de novo data available
Still missing
  • Parental testing data unavailable
PS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB labels variant Likely Oncogenic (Likely Loss-of-function) but this reflects curated gene-level inference
  • No publication with variant-specific functional characterization identified
Still missing
  • No functional studies have directly tested this variant
Sources
oncokb ↗
PS4 This variant is absent from ClinVar and gnomAD population databases. No case-control data demonstrating enrichment in affected individuals is available. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar and all gnomAD databases
Still missing
  • No affected vs. control comparison available
Sources
clinvar ↗gnomad_v2 ↗gnomad_v4 ↗
PM1 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. Details ▾Hide ▴
Evidence considered
  • Not a cancerhotspots.org significant hotspot
  • Truncation removes extreme C-terminus outside annotated functional domains
Still missing
  • Functional significance of the C-terminal ~40 residues is not well characterized
PM5 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. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search yielded zero same-residue comparator variants in ClinVar
Sources
pm5_candidatesclinvar ↗
PM6 No de novo observation has been reported for this variant; assumed de novo not applicable without at least one report. Details ▾Hide ▴
Evidence considered
  • No de novo data available
Still missing
  • Parental testing data unavailable
PP1 No segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
  • No family segregation data
Still missing
  • Family studies with segregation analysis needed
PP3 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.38 (borderline
  • below 0.5 confident threshold)
  • REVEL and BayesDel not applicable to duplication variant
  • HCI prior not available for SETD2
Sources
spliceai ↗
PP4 No patient phenotype or family history is available for assessment against the disease-specific presentation of SETD2 overgrowth syndrome. Details ▾Hide ▴
Evidence considered
  • No clinical phenotype data provided
Still missing
  • Patient phenotype and family history needed
PP5 This variant is absent from ClinVar. No reputable source has independently reported it as pathogenic. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no pathogenic classification from any source
Sources
clinvar ↗
BA1 The variant is absent from all population databases, with an allele frequency far below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • Absent from all gnomAD databases
  • allele frequency effectively zero
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 The variant is absent from population databases; allele frequency does not exceed the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
  • Absent from all gnomAD databases
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 The variant has not been observed in any healthy adult individual; absent from gnomAD. Details ▾Hide ▴
Evidence considered
  • Variant not observed in any individual in gnomAD
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 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. Details ▾Hide ▴
Evidence considered
  • No functional studies identified for this variant
Still missing
  • Functional characterization of this variant is absent
BS4 No family segregation data are available to demonstrate lack of cosegregation with disease. Details ▾Hide ▴
Evidence considered
  • No segregation data
Still missing
  • Family segregation analysis needed
BP2 No co-occurrence data are available; the variant has not been observed in trans with a pathogenic SETD2 variant or in any individual. Details ▾Hide ▴
Evidence considered
  • No co-occurrence data available
Still missing
  • Observation in trans or cis with known pathogenic variants needed
BP4 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. Details ▾Hide ▴
Evidence considered
  • Variant creates premature stop codon p.Lys2525Ter
  • SpliceAI does not predict a benign silent effect
Sources
spliceai ↗
BP5 No data on an alternate molecular basis for disease in a case harboring this variant are available. Details ▾Hide ▴
Evidence considered
  • No case with alternate molecular diagnosis identified
Still missing
  • Case-level molecular workup needed
BP6 This variant is absent from ClinVar. No reputable source has reported it as benign. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no benign classification from any source
Sources
clinvar ↗
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/ANo data for a recessive disorder trans observation; SETD2 overgrowth syndrome is autosomal dominant. Details ▾Hide ▴

No further detail was recorded.

PM4 N/AThis duplication creates a frameshift and premature termination, not an in-frame insertion/deletion or stop-loss variant. Protein truncation is assessed under PVS1. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 applies specifically to missense variants in genes with a low rate of benign missense variation. This is a truncating (nonsense) variant. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. This is a truncating variant and does not qualify for BP1 consideration. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 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. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a duplication leading to a frameshift and premature termination, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 is not a standard ACMG/AMP 2015 criterion. No well-established in vitro/in vivo functional study with replication is available for this variant. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
SETD2
Transcript
NM_014159.6
Coding (HGVS c.)
NM_014159.6:c.7572dup
Protein (HGVS p.)
NP_054878.5:p.(Lys2525Ter)
GRCh38
chr3:47017215 T>TA
GRCh37
chr3:47058705 T>TA
COSMIC
COSV57443657

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 +39 bp
0.380
SpliceAI acceptor gainat -214 bp
0.010
SpliceAI donor lossat +423 bp
0.210
SpliceAI donor gainat -155 bp
0.000
Pangolin splice lossmagnitude shown
-0.500
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.38 (borderline
  • below 0.5 confident threshold)
  • REVEL and BayesDel not applicable to duplication variant
  • HCI prior not available for SETD2
Sources
spliceai ↗
BP4 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. Details ▾Hide ▴
Evidence considered
  • Variant creates premature stop codon p.Lys2525Ter
  • SpliceAI does not predict a benign silent effect
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a duplication leading to a frameshift and premature termination, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.38).

3 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.
    Reports recurrent SETD2 mutations in pediatric high-grade gliomas using whole-exome sequencing. NM_014159.6:c.7572dup was not identified in this paper.
    Does not name this variant
    PMID 23417712 ↗
  • Identification of functional cooperative mutations of SETD2 in human acute leukemia.
    Identifies cooperative SETD2 mutations in MLL-rearranged acute leukemia using whole-genome sequencing. NM_014159.6:c.7572dup 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.
    Demonstrates that SETD2 loss-of-function promotes branched evolution in clear cell renal carcinoma through replication stress and impaired DNA repair. NM_014159.6:c.7572dup was not identified in this paper.
    Does not name this variant
    PMID 25728682 ↗

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 0.380 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 is absent from ClinVar.

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.38).

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; COSV57443657, n = 3 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.