About KMT2A
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
KMT2A c.8956G>A, p.(Glu2986Lys)
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: 0
Benign evidence criteria: 0
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
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: none; combination = no applied criteria, 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
445 / 1,614,106 alleles
gnomAD v4.1: 445 / 1,614,106 alleles. Recorded AF 0.000275694. Recorded homozygote count 1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000240616; MAF= 0.02406%, 68/282608 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000434223; MAF= 0.04342%, 56/128966 alleles, homozygotes = 0); grpmax FAF= 0.00035778.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.000108613; MAF= 0.01086%, 2/18414 alleles, homozygotes = 0) and has highest observed frequency in the nfe population (AF= 0.000170416; grpmax FAF95= 3.01e-05).
No listed criterion applied
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions
1 Benign · 1 Likely benign.
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. KMT2A, a histone methyltransferase, is altered by mutation or deletion in various solid tumors, and by chromosomal rearrangement in various hematologi
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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.
28 criteria with recorded statuses: 0 met · 6 not met · 18 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The KMT2A c.8956G>A (p.Glu2986Lys) variant has been reported in ClinVar with benign and likely benign single-submitter classifications.
This variant is present in population databases, with gnomAD v2.1 AF 0.02406% (68/282608) and gnomAD v4.1 AF 0.02757% (445/1614106), including 1 homozygote in gnomAD v4.1.
Available hotspot review did not identify this residue within a statistically significant mutational hotspot.
In silico results are inconclusive overall: SpliceAI predicts no significant splice effect (max delta score 0.00), while REVEL 0.527 and BayesDel 0.269249 do not provide a concordant benign or pathogenic signal.
No criteria match.
Not met · 6 · evaluated, threshold not reached
PM1 Available hotspot review did not identify this residue within a statistically significant mutational hotspot or other well-established critical functional region. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM1
Evidence considered
- Cancer Hotspots review reported no hotspot row for KMT2A E2986.
Sources
PM2 This variant is present in population databases rather than absent or near-absent, with gnomAD v2.1 AF 0.02406% (68/282608) and gnomAD v4.1 AF 0.02757% (445/1614106), including 1 homozygote in v4.1. Although these frequencies are below a 0.1% rarity threshold, the repeated population observation does not support PM2. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM2
Evidence considered
- Observed in both gnomAD releases with multiple alleles and one homozygote.
Sources
PP3 Computational results are not concordantly damaging. SpliceAI predicts no significant splice impact (max delta score 0.00), while REVEL is 0.527 and BayesDel is 0.269249, which do not provide a clear, internally consistent damaging signal. Details ▾Hide ▴
Rule
Generic ACMG/AMP PP3
Evidence considered
- SpliceAI max delta 0.00.
- REVEL 0.527.
- BayesDel 0.269249.
Sources
BA1 Population frequency does not reach a stand-alone benign threshold. The highest observed gnomAD population frequency is 0.04342% in v2.1 and 0.03491% in v4.1, both well below 1%. Details ▾Hide ▴
Rule
Generic ACMG/AMP BA1
Evidence considered
- Highest observed subpopulation frequencies remain below 1%.
Sources
BS1 Population frequency is not above a strong benign threshold. The highest observed gnomAD population frequency is 0.04342% in v2.1 and 0.03491% in v4.1, both below 0.3%. Details ▾Hide ▴
Rule
Generic ACMG/AMP BS1
Evidence considered
- Highest observed subpopulation frequencies remain below 0.3%.
Sources
BP4 Computational evidence does not support a concordant benign interpretation. SpliceAI predicts no splice effect (max delta score 0.00), but REVEL 0.527 and BayesDel 0.269249 are not clearly benign and do not provide a consistent benign signal. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP4
Evidence considered
- SpliceAI max delta 0.00.
- REVEL 0.527.
- BayesDel 0.269249.
Sources
Not assessed · 18 · no assessment recorded
PS1 No validated evidence was identified showing that a different nucleotide change causing the same p.Glu2986Lys amino acid substitution is already established as pathogenic or likely pathogenic. Details ▾Hide ▴
Rule
Generic ACMG/AMP PS1
Still missing
- A same-amino-acid pathogenic comparator was not identified in the available evidence.
PS2 No confirmed de novo occurrence data were identified for this variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP PS2
Still missing
- No parental testing or confirmed maternity/paternity data were identified.
PS3 No published functional study was identified that directly tested the effect of this specific variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP PS3
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence.
Still missing
- Variant-specific functional assay data were not identified.
Sources
PS4 No case-control or statistically enriched case series evidence was identified for this variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP PS4
Evidence considered
- ClinVar contains low-level clinical assertions but no case-control signal.
Still missing
- No affected-case enrichment data were identified.
Sources
PM3 No recessive-phase or trans observation data were identified for this variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM3
Still missing
- No confirmed trans observations with a pathogenic variant were identified.
PM6 No assumed de novo occurrence data were identified for this variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM6
Still missing
- No de novo report without full parental confirmation was identified.
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP PP1
Still missing
- No family segregation evidence was identified.
PP2 Available evidence does not establish a gene-specific setting in which missense variation is a common disease mechanism and benign missense variation is rare enough to support PP2. Details ▾Hide ▴
Rule
Generic ACMG/AMP PP2
Still missing
- No gene-specific missense constraint framework was identified.
PP4 No phenotype or clinical presentation data were provided that would support a highly specific KMT2A-related syndrome attribution for this variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP PP4
Still missing
- No case phenotype data were identified.
PP5 No pathogenic assertion from an expert panel or other sufficiently authoritative source was identified for use under PP5. Details ▾Hide ▴
Rule
Generic ACMG/AMP PP5
Evidence considered
- ClinVar shows only single-submitter benign/likely benign assertions.
Still missing
- No expert-panel pathogenic classification was identified.
Sources
BS2 Population databases show this variant in controls, including 1 homozygote in gnomAD v4.1, but no dataset-specific evidence was identified confirming unaffected status and penetrance assumptions needed to apply BS2 confidently. Details ▾Hide ▴
Rule
Generic ACMG/AMP BS2
Evidence considered
- gnomAD v4.1 reports 1 homozygote.
Still missing
- No confirmed unaffected-individual dataset matched to BS2 requirements was identified.
Sources
BS3 No well-established functional study was identified showing a normal effect for this specific variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP BS3
Evidence considered
- No reviewed variant-specific functional evidence was identified.
Still missing
- Variant-specific benign functional evidence was not identified.
Sources
BS4 No evidence was identified showing lack of segregation with disease in affected relatives. Details ▾Hide ▴
Rule
Generic ACMG/AMP BS4
Still missing
- No family segregation study was identified.
BP1 This is a missense variant, but available evidence does not show that KMT2A disease is driven predominantly by truncating variants with missense changes generally being benign. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP1
Still missing
- No gene-specific evidence supporting BP1 was identified.
BP2 No phase information or co-occurrence data were identified for this variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP2
Still missing
- No confirmed cis/trans co-occurrence evidence was identified.
BP3 No evidence was identified placing this variant in a repetitive region without known function. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP3
Still missing
- No repeat-region annotation relevant to BP3 was identified.
BP5 No alternate molecular diagnosis or independent cause for disease was identified that would support BP5. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP5
Still missing
- No alternative molecular explanation was identified.
BP6 ClinVar contains benign and likely benign single-submitter assertions, but no expert-panel benign classification or primary evidence set sufficient for independent benign criterion use was identified. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP6
Evidence considered
- ClinVar shows one benign and one likely benign single-submitter assertion.
Still missing
- No expert-panel or otherwise definitive benign source was identified.
Sources
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, and the generic PVS1 framework applies to predicted loss-of-function variant types such as nonsense, frameshift, or canonical +/-1,2 splice variants. Available gene-level context supports KMT2A loss of function as a disease mechanism, but that does not make PVS1 applicable to this amino acid substitution. Details ▾Hide ▴
Rule
Generic ACMG/AMP PVS1 with ClinGen SVI PVS1 fallback
Evidence considered
- KMT2A loss of function is an established germline disease mechanism.
- The variant-specific PVS1 scaffold states this substitution is outside the default null-variant buckets.
Sources
PM4 N/AThis variant is a single amino acid substitution and does not cause a protein length change from an in-frame insertion/deletion or stop-loss event. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM4
PM5 N/AAvailable review materials could not confirm that classic same-residue PM5 logic should be applied for this gene and variant, and no validated same-residue pathogenic comparator was identified. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM5
Evidence considered
- PM5 candidate review explicitly marked classic same-residue PM5 semantics as unconfirmed.
Sources
pm5_candidates
BP7 N/AThis variant is a missense substitution, so BP7 for synonymous or deep intronic variants does not apply. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP7
Identifiers
- Gene
- KMT2A
- Transcript
- NM_005933.3
- Coding (HGVS c.)
- NM_005933.3:c.8956G>A
- Protein (HGVS p.)
- NP_005924.2:p.(Glu2986Lys)
- GRCh38
- chr11:118504857 G>A
- GRCh37
- chr11:118375572 G>A
- ClinVar
- 444273
Gene diagram
Every interpreted variant in KMT2A, mapped onto the exon structure of NM_005933.3. Select a row to find it on the plot.
KMT2ANM_005933.3
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 KMT2A
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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
445 / 1,614,106 alleles
AF 0.000276 · 1 homozygotes · FAF 0.000321
gnomAD v2.1
68 / 282,608 alleles
AF 0.000241 · 0 homozygotes · FAF 0.000358
gnomAD-Canada v1.0
2 / 18,414 alleles
AF 0.000109 · 0 homozygotes · FAF 3.01e-05
By genetic ancestry
gnomAD v4.1
AF 0.00028 · 445 / 1,614,106 alleles · 1 hom · FAF 0.00032
| European (non-Finnish)412 / 1,180,010 | 0.000351 hom |
| Admixed American16 / 60,020 | 0.00027 |
| Remaining individuals10 / 62,506 | 0.00016 |
| African/African American4 / 74,994 | 5.3e-05 |
| European (Finnish)3 / 64,030 | 4.7e-05 |
0 alternate alleles recorded in 5 other groups: Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00024 · 68 / 282,608 alleles · 0 hom · FAF 0.00036
| European (non-Finnish)56 / 128,966 | 0.00043 |
| Admixed American10 / 35,428 | 0.00028 |
| Remaining individuals2 / 7,218 | 0.00028 |
0 alternate alleles recorded in 5 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian.
gnomAD-Canada
AF 0.00011 · 2 / 18,414 alleles · 0 hom · FAF 3e-05
| nfe2 / 11,736 | 0.00017 |
0 alternate alleles recorded in 8 other groups: afr, amr, asj, eas, fin, mid, oth, sas.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000275694; MAF= 0.02757%, 445/1614106 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00034915; MAF= 0.03491%, 412/1180010 alleles, homozygotes = 1); grpmax FAF= 0.00032126.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000240616; MAF= 0.02406%, 68/282608 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000434223; MAF= 0.04342%, 56/128966 alleles, homozygotes = 0); grpmax FAF= 0.00035778.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.000108613; MAF= 0.01086%, 2/18414 alleles, homozygotes = 0) and has highest observed frequency in the nfe population (AF= 0.000170416; grpmax FAF95= 3.01e-05).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.527
- BayesDel
- 0.269
How the predictions were used
PP3 Computational results are not concordantly damaging. SpliceAI predicts no significant splice impact (max delta score 0.00), while REVEL is 0.527 and BayesDel is 0.269249, which do not provide a clear, internally consistent damaging signal. Details ▾Hide ▴
Rule
Generic ACMG/AMP PP3
Evidence considered
- SpliceAI max delta 0.00.
- REVEL 0.527.
- BayesDel 0.269249.
Sources
BP4 Computational evidence does not support a concordant benign interpretation. SpliceAI predicts no splice effect (max delta score 0.00), but REVEL 0.527 and BayesDel 0.269249 are not clearly benign and do not provide a consistent benign signal. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP4
Evidence considered
- SpliceAI max delta 0.00.
- REVEL 0.527.
- BayesDel 0.269249.
Sources
BP7 N/AThis variant is a missense substitution, so BP7 for synonymous or deep intronic variants does not apply. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP7
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.527. BayesDel score = 0.269249.
1 paper record 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
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
445 / 1,614,106 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
1 Benign · 1 Likely benign
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/variation/444273/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-118375572-G-A?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-118504857-G-A?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/11-118504857-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005933.3%3Ac.8956…
- OncoKB ↗www.oncokb.org/gene/KMT2A/E2986K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=KMT2A+c.8956G%3EA
- 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
This variant is present in gnomAD v4.1 (AF= 0.000275694; MAF= 0.02757%, 445/1614106 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00034915; MAF= 0.03491%, 412/1180010 alleles, homozygotes = 1); grpmax FAF= 0.00032126.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000240616; MAF= 0.02406%, 68/282608 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000434223; MAF= 0.04342%, 56/128966 alleles, homozygotes = 0); grpmax FAF= 0.00035778.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.000108613; MAF= 0.01086%, 2/18414 alleles, homozygotes = 0) and has highest observed frequency in the nfe population (AF= 0.000170416; grpmax FAF95= 3.01e-05).
ClinVar
This variant has been reported in ClinVar as Benign (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 444273)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.527. BayesDel score = 0.269249.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. KMT2A, a histone methyltransferase, is altered by mutation or deletion in various solid tumors, and by chromosomal rearrangement in various hematologi
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.