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KMT2A
Final classification
VUS
KMT2A c.8956G>A · p.Glu2986Lys
KMT2A

The KMT2A c.8956G>A (p.Glu2986Lys) variant has been reported in ClinVar with benign and likely benign single-submitter classifications.

Gene
KMT2A
Transcript
NM_005933.3
HGVS · transcript:coding
NM_005933.3:c.8956G>A
Consequence
N/A
GRCh38
chr11:118504857 G>A
GRCh37
chr11:118375572 G>A
Basis 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. ▾
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.
Classification rationale
VUS
KMT2A c.8956G>A

The KMT2A c.8956G>A (p.Glu2986Lys) variant has been reported in ClinVar with benign and likely benign single-submitter classifications.1 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 v4.1.2 Available hotspot review did not identify this residue within a statistically significant mutational hotspot.3 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.4

1 clinvar ↗
2 gnomad_v2 ↗gnomad_v4 ↗
3 hotspots ↗
4 spliceai ↗revelbayesdel
Gene diagram · NM_005933.3 · variants mapped to exon structure
KMT2A NM_005933.3
Fetching transcript structure from UCSC…
Applied criteria · 0 met · select any tile
Met
Not met
Not assessed
N/A
Strength very strong supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
    Gaps remaining
      Rule
      —
      Research & evidence
      Population frequency
      gnomAD v4.1 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      gnomAD v2.1
      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.
      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.
      🇨🇦 CA
      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).
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      0.028% · 445 / 1,614,106
      1 hom · FAF 0.032%
      European (non-Finnish)
      412 / 1,180,010
      0.035%
      1 hom
      Admixed American
      16 / 60,020
      0.027%
      Remaining individuals
      10 / 62,506
      0.016%
      African/African American
      4 / 74,994
      0.0053%
      European (Finnish)
      3 / 64,030
      0.0047%
      + 5 not observed (Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
      gnomAD v2.1
      0.024% · 68 / 282,608
      0 hom · FAF 0.036%
      European (non-Finnish)
      56 / 128,966
      0.043%
      Admixed American
      10 / 35,428
      0.028%
      Remaining individuals
      2 / 7,218
      0.028%
      + 5 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian)
      gnomAD Canada 🇨🇦
      0.011% · 2 / 18,414
      0 hom · FAF 0.003%
      European (non-Finnish)
      2 / 11,736
      0.017%
      + 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals, South Asian)
      gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
      ClinVar screenshot
      ClinVar
      This variant has been reported in ClinVar as Benign (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 444273)
      ClinVar ↗
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.527. BayesDel score = 0.269249.
      SpliceAI ↗
      Functional / OncoKB screenshot
      Functional Unknown Oncogenic Effect
      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
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Cancer hotspots screenshot
      Cancer hotspots
      Somatic evidence Not in COSMIC / hotspots
      COSMIC
      This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
      Hotspots
      This variant does not lie in a statistically significant hotspot.
      COSMIC ↗ Hotspots ↗
      Sources & reference links
      8Sources
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      gnomAD-Canada
      SpliceAI
      OncoKB
      COSMIC
      Cancer hotspots
      Triaged references · 1 PMID not cited in assessment
      28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR