NM_005933.3:c.8956G>A

KMT2A · NP_005924.2:p.(Glu2986Lys) · NM_005933.3

GRCh37: chr11:118375572 G>A · GRCh38: chr11:118504857 G>A

Gene: KMT2A Transcript: NM_005933.3

Final call

VUS

Variant details

Gene

KMT2A

Transcript

NM_005933.3

Protein

NP_005924.2:p.(Glu2986Lys)

gnomAD AF

0.0002756944091651973 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This 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.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	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	Not assessed	No confirmed de novo occurrence data were identified for this variant.
PS3	Not assessed	No published functional study was identified that directly tested the effect of this specific variant.	oncokb
PS4	Not assessed	No case-control or statistically enriched case series evidence was identified for this variant.	clinvar PMID:28492532
PM1	Not met	Available hotspot review did not identify this residue within a statistically significant mutational hotspot or other well-established critical functional region.	hotspots
PM2	Not met	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.	gnomad_v2 gnomad_v4
PM3	Not assessed	No recessive-phase or trans observation data were identified for this variant.
PM4	N/A	This 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.
PM5	N/A	Available 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.	pm5_candidates
PM6	Not assessed	No assumed de novo occurrence data were identified for this variant.
PP1	Not assessed	No segregation data were identified for this variant.
PP2	Not assessed	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	Not met	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.	spliceai revel bayesdel
PP4	Not assessed	No phenotype or clinical presentation data were provided that would support a highly specific KMT2A-related syndrome attribution for this variant.
PP5	Not assessed	No pathogenic assertion from an expert panel or other sufficiently authoritative source was identified for use under PP5.	clinvar
BA1	Not met	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%.	gnomad_v2 gnomad_v4
BS1	Not met	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%.	gnomad_v2 gnomad_v4
BS2	Not assessed	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.	gnomad_v4
BS3	Not assessed	No well-established functional study was identified showing a normal effect for this specific variant.	oncokb
BS4	Not assessed	No evidence was identified showing lack of segregation with disease in affected relatives.
BP1	Not assessed	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	Not assessed	No phase information or co-occurrence data were identified for this variant.
BP3	Not assessed	No evidence was identified placing this variant in a repetitive region without known function.
BP4	Not met	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.	spliceai revel bayesdel
BP5	Not assessed	No alternate molecular diagnosis or independent cause for disease was identified that would support BP5.
BP6	Not assessed	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.	clinvar PMID:28492532
BP7	N/A	This variant is a missense substitution, so BP7 for synonymous or deep intronic variants does not apply.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.