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 applied · 24 assessed

Applied · 0

No criteria were applied for this variant.

Assessed · not applied

Pathogenic

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.

PS2 No confirmed de novo occurrence data were identified for this variant.

PS3 No published functional study was identified that directly tested the effect of this specific variant.

PS4 No case-control or statistically enriched case series evidence was identified for this variant.

PM1 Available hotspot review did not identify this residue within a statistically significant mutational hotspot or other well-established critical functional region.

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.

PM3 No recessive-phase or trans observation data were identified for this variant.

PM6 No assumed de novo occurrence data were identified for this variant.

PP1 No segregation data were identified for this variant.

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.

PP3 Computational results are not concordantly damaging.

PP4 No phenotype or clinical presentation data were provided that would support a highly specific KMT2A-related syndrome attribution for this variant.

PP5 No pathogenic assertion from an expert panel or other sufficiently authoritative source was identified for use under PP5.

Benign

BA1 Population frequency does not reach a stand-alone benign threshold.

BS1 Population frequency is not above a strong benign threshold.

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.

BS3 No well-established functional study was identified showing a normal effect for this specific variant.

BS4 No evidence was identified showing lack of segregation with disease in affected relatives.

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.

BP2 No phase information or co-occurrence data were identified for this variant.

BP3 No evidence was identified placing this variant in a repetitive region without known function.

BP4 Computational evidence does not support a concordant benign interpretation.

BP5 No alternate molecular diagnosis or independent cause for disease was identified that would support BP5.

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.

N/A · 4 PVS1 · PM4 · PM5 · BP7

Research & evidence

Population frequency

gnomAD v4.1

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

This variant has been reported in ClinVar as Benign (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 444273)

ClinVar ↗

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 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

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

Re-run this variant?