About SETD2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SETD2 c.5746C>T, p.(Pro1916Ser)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_014159.6:c.5746C>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, meeting the PM2 threshold of <0.1% population frequency under the generic ACMG/AMP framework.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on the gene product: REVEL score 0.204 (below 0.5 threshold), BayesDel score -0.265772 (negative, benign-leaning), and SpliceAI max delta score 0.00 (no predicted splice impact). Under generic ACMG/AMP, BP4 applies when multiple in silico tools predict a benign effect.
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: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SETD2, an H3K36 trimethylase, is altered in a variety of cancer types.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
4 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV57435928, n = 4 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
27 criteria with recorded statuses: 2 met · 20 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_014159.6:c.5746C>T (p.Pro1916Ser) in SETD2 is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_Supporting).
Multiple in silico tools predict a benign effect: REVEL 0.204, BayesDel -0.265772, and SpliceAI max delta 0.00 (BP4_Supporting).
One supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) result in conflicting evidence. Under generic ACMG/AMP 2015 classification rules, this yields a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingNM_014159.6:c.5746C>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, meeting the PM2 threshold of <0.1% population frequency under the generic ACMG/AMP framework. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes). Absent from gnomAD v4.1 (exomes/genomes). Absent from gnomAD-Canada v1.0.
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product: REVEL score 0.204 (below 0.5 threshold), BayesDel score -0.265772 (negative, benign-leaning), and SpliceAI max delta score 0.00 (no predicted splice impact). Under generic ACMG/AMP, BP4 applies when multiple in silico tools predict a benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.204 (benign-leaning). BayesDel: -0.265772 (benign-leaning). SpliceAI: max delta 0.00 (no splice effect).
Sources
Not met · 20 · evaluated, threshold not reached
PS2 No de novo evidence is available for this variant. No publications or clinical databases report de novo occurrence of NM_014159.6:c.5746C>T. Details ▾Hide ▴
Evidence considered
- No de novo data found in ClinVar or literature.
Still missing
- No parental testing data available.
Sources
PS3 No well-established functional studies have been performed on this specific variant (p.Pro1916Ser) or a systematically characterized range that includes position 1916. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. In silico scores (REVEL 0.204, BayesDel -0.265772) are benign-leaning and do not constitute functional evidence for PS3. Details ▾Hide ▴
Evidence considered
- OncoKB: no variant-specific functional data. REVEL 0.204 (benign-leaning). BayesDel -0.265772 (benign-leaning). No publications with functional characterization of this variant or its residue range identified.
Still missing
- No functional studies available for NM_014159.6:c.5746C>T or position 1916.
Sources
PS4 Variant prevalence in affected individuals has not been established. This variant is absent from ClinVar and absent from gnomAD. No case-control studies demonstrating enrichment in affected individuals are available. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar. Absent from gnomAD v2.1 and v4.1.
Still missing
- No case-control data available.
Sources
PM1 Position 1916 is C-terminal to the SET domain of SETD2 and does not lie within a well-characterized critical functional domain. Cancerhotspots.org does not identify this residue as a statistically significant hotspot. No CSPEC/VCEP framework identifies position 1916 as a mutational hotspot. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: no significant hotspot at P1916. Position 1916 is outside the SET domain (approx. aa 1500-1700). No CSPEC/VCEP domain-level guidance available.
Still missing
- No domain-level functional characterization includes position 1916.
PM5 No different pathogenic missense variant at SETD2 amino acid position 1916 has been identified in ClinVar. Automated PM5 candidate harvesting confirmed zero same-residue comparator candidates. Details ▾Hide ▴
Evidence considered
- PM5 candidate harvesting: 0 same-residue candidates
- 0 candidates total. ClinVar has no variants at position 1916.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo evidence is available for this variant. PM6 requires a de novo observation with confirmed maternity and paternity. Details ▾Hide ▴
Evidence considered
- No de novo reports in ClinVar or literature.
Still missing
- No parental testing data available.
Sources
PP1 No segregation data are available for this variant. PP1 requires co-segregation of the variant with disease in multiple affected family members. Details ▾Hide ▴
Evidence considered
- No family studies or segregation data identified.
Still missing
- No segregation analysis data available.
PP2 PP2 requires a CSPEC/VCEP-defined low rate of benign missense variation and high rate of pathogenic missense variation for the gene. No CSPEC/VCEP framework exists for SETD2, and insufficient data are available to apply this criterion generically. Details ▾Hide ▴
Evidence considered
- No CSPEC/VCEP framework for SETD2. Gene-level missense constraint insufficiently characterized for generic PP2.
Still missing
- No CSPEC/VCEP-defined PP2 threshold for SETD2.
PP3 Multiple in silico predictors suggest a benign effect: REVEL score 0.204 (below the 0.5 pathogenic threshold), BayesDel score -0.265772 (negative, benign-leaning), and SpliceAI max delta score 0.00 (no predicted splice impact). These do not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.204 (benign-leaning). BayesDel: -0.265772 (benign-leaning). SpliceAI: max delta 0.00 (no splice effect).
Sources
PP4 No specific patient phenotype information is available for this case. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
- No phenotype data provided for this case.
Still missing
- Patient phenotype and clinical presentation not available.
PP5 This variant is absent from ClinVar. PP5 requires a reputable source (≥3-star ClinVar expert panel) to have classified the variant as pathogenic. Details ▾Hide ▴
BA1 This variant is absent from gnomAD (v2.1, v4.1, and gnomAD-Canada). BA1 requires an allele frequency >1% in population databases. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- v4.1
- and gnomAD-Canada. Frequency 0%
- does not meet >1% BA1 threshold.
Sources
BS1 This variant is absent from gnomAD. BS1 requires an allele frequency >0.3% for a dominant disorder (>0.5% for recessive) in population databases. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- v4.1
- and gnomAD-Canada. Frequency 0%
- does not meet >0.3% BS1 threshold.
Sources
BS2 No homozygous or hemizygous observations of this variant in healthy individuals are available. BS2 requires observation in a healthy adult at a frequency consistent with full penetrance for recessive/dominant disease. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD
- no homozygous or hemizygous observations available.
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing exist for this variant. In silico predictions (REVEL, BayesDel) are computational and do not constitute functional studies under BS3. Details ▾Hide ▴
Evidence considered
- REVEL 0.204 and BayesDel -0.265772 are benign-leaning in silico predictors
- not functional studies. OncoKB: no variant-specific functional data.
Still missing
- No experimental functional studies available for this variant.
Sources
BS4 No segregation data demonstrating lack of co-segregation with disease are available for this variant. Details ▾Hide ▴
Evidence considered
- No segregation analysis or family studies identified.
Still missing
- No family studies or segregation data available.
BP1 No evidence that this missense variant occurs in trans with a pathogenic SETD2 variant. BP1 requires a missense variant in a gene where truncating variants cause disease to be observed in trans with a pathogenic variant. Details ▾Hide ▴
Evidence considered
- No trans configuration data available.
Still missing
- No phasing data available.
BP2 No observation of this variant in trans with a pathogenic SETD2 variant or in cis with a pathogenic variant in a recessive disorder. No data available. Details ▾Hide ▴
Evidence considered
- No trans or cis configuration data available.
Still missing
- No phasing data available.
BP5 No alternative molecular cause for the phenotype has been identified in this case. BP5 requires a variant found in a case with an alternative molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No alternative molecular cause identified or reported.
Still missing
- No data on alternative molecular causes in this case.
BP6 This variant is absent from ClinVar. BP6 requires a reputable source (≥3-star ClinVar expert panel) to have classified the variant as benign or likely benign. Details ▾Hide ▴
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is restricted to null variants (nonsense, frameshift, canonical splice ±1/2, initiation codon, single/multi-exon deletion). NM_014159.6:c.5746C>T is a missense substitution (p.Pro1916Ser) and does not fall into any PVS1-eligible variant bucket per PMC6185798. Details ▾Hide ▴
Evidence considered
- Missense variant
- variant_bucket=other
- not eligible for generic PVS1 framework application.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PS1 N/ANo known pathogenic variant at SETD2 amino acid position 1916 with a different nucleotide change exists in ClinVar. PS1 requires a different nucleotide change at the same amino acid position that has been classified as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar contains no entries for this variant or any variant at amino acid position 1916 of SETD2.
Sources
BP3 N/ASkipped: trivially not applicable per instruction. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_014159.6:c.5746C>T is a missense variant (p.Pro1916Ser), not synonymous. Details ▾Hide ▴
Evidence considered
- Missense variant (Pro1916Ser)
- not synonymous. BP7 not applicable.
PS5 N/APS5 requires a ClinVar expert panel pathogenic classification for a variant at the same residue with a different amino acid change. This variant is absent from ClinVar, and no PM5 candidate comparators exist at position 1916. Details ▾Hide ▴
Evidence considered
- ClinVar has no entries for this variant. PM5 candidate harvesting returned no same-residue candidates.
Sources
clinvar ↗pm5_candidates
Identifiers
- Gene
- SETD2
- Transcript
- NM_014159.6
- Coding (HGVS c.)
- NM_014159.6:c.5746C>T
- Protein (HGVS p.)
- NP_054878.5:p.(Pro1916Ser)
- GRCh38
- chr3:47084034 G>A
- GRCh37
- chr3:47125524 G>A
- COSMIC
- COSV57435928
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…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in SETD2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
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
Other predictors
- REVEL
- 0.204
- BayesDel
- -0.266
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product: REVEL score 0.204 (below 0.5 threshold), BayesDel score -0.265772 (negative, benign-leaning), and SpliceAI max delta score 0.00 (no predicted splice impact). Under generic ACMG/AMP, BP4 applies when multiple in silico tools predict a benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.204 (benign-leaning). BayesDel: -0.265772 (benign-leaning). SpliceAI: max delta 0.00 (no splice effect).
Sources
PP3 Multiple in silico predictors suggest a benign effect: REVEL score 0.204 (below the 0.5 pathogenic threshold), BayesDel score -0.265772 (negative, benign-leaning), and SpliceAI max delta score 0.00 (no predicted splice impact). These do not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.204 (benign-leaning). BayesDel: -0.265772 (benign-leaning). SpliceAI: max delta 0.00 (no splice effect).
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_014159.6:c.5746C>T is a missense variant (p.Pro1916Ser), not synonymous. Details ▾Hide ▴
Evidence considered
- Missense variant (Pro1916Ser)
- not synonymous. BP7 not applicable.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.204. BayesDel score = -0.265772.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
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 0.000
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_014159.6%3Ac.5746C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-47125524-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-47084034-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-47084034-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_014159.6%3Ac.5746…
- OncoKB ↗www.oncokb.org/gene/SETD2/P1916S
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=153170633
- Cancer hotspots ↗www.cancerhotspots.org/
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 no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.204. BayesDel score = -0.265772.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SETD2, an H3K36 trimethylase, is altered in a variety of cancer types.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57435928, n = 4 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.