NM_005933.3:c.8878G>T (p.Val2960Leu) is a missense variant in exon 27 of KMT2A. This variant is absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting).1 Multiple lines of computational evidence predict no deleterious effect: REVEL score 0.178, BayesDel score -0.147545, and SpliceAI max delta 0.00 (BP4_Supporting).2 The variant is absent from ClinVar; no pathogenic or benign classification has been assigned by any clinical submitter.3 No functional studies, segregation data, de novo observations, or case reports were identified for this specific variant in the literature. Under generic ACMG/AMP 2015 combination rules, PM2_Supporting and BP4_Supporting are in opposing directions and do not combine to reach a conclusive classification. The variant is classified as a Variant of Uncertain Significance (VUS).4
KMT2A
Final classification
VUS
KMT2A c.8878G>T · p.Val2960Leu
KMT2A
NM_005933.3:c.8878G>T (p.Val2960Leu) is a missense variant in exon 27 of KMT2A.
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.
Classification rationale
PM2
BP4
VUS
KMT2A c.8878G>T
PM2 + BP4
→
VUS
Gene diagram
· NM_005933.3 · variants mapped to exon structure
KMT2A
NM_005933.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 18 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 (exome) and gnomAD v4.1 (exome) population databases, consistent with PM2 under generic ACMG/AMP 2015 interpretation.
Absent from gnomAD v2.1 and v4.1 (search_status: absent).Absent from gnomAD-Canada v1.0.
✓
BP4
supporting
Benign
Multiple lines of computational evidence predict no deleterious impact. REVEL score is 0.178 (below 0.5 pathogenic threshold), BayesDel score is -0.147545 (negative score indicates benign), and SpliceAI predicts no splice impact (max delta score 0.00).
REVEL: 0.178. BayesDel: -0.147545. SpliceAI max delta: 0.00.
Assessed · not applied
Pathogenic
PS2
No evidence of de novo occurrence for NM_005933.3:c.8878G>T.
PS3
No well-established in vitro or in vivo functional studies demonstrating a damaging effect on the gene or gene product were identified for this variant.
PS4
The prevalence of this variant in affected individuals has not been established.
PM1
The variant does not lie in a known mutational hotspot or a critical functional domain with a statistically significant enrichment of pathogenic variation.
PM6
No confirmed de novo observation for this variant was identified in the literature.
PP1
No cosegregation data with disease in multiple affected family members is available for this variant.
PP2
HCI prior is not supported for the KMT2A gene (gene_not_supported).
PP3
Multiple lines of computational evidence do not support a deleterious effect.
PP4
No patient phenotype data specific to this variant are available.
PP5
The variant is absent from ClinVar.
Benign
BA1
The variant is absent from gnomAD population databases.
BS1
The variant is absent from gnomAD population databases.
BS2
No data are available on healthy adult controls carrying this variant.
BS3
No well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing have been identified for this variant.
BS4
No segregation data demonstrating lack of cosegregation with disease are available for this variant.
BP2
No observation of this variant in trans with a known pathogenic variant in a gene associated with a recessive disorder has been reported.
BP5
No alternative molecular basis for disease has been identified in a case harboring this variant.
BP6
No reputable source classifies this variant as benign or likely benign.
N/A · 8
PVS1 · PS1 · PM3 · PM4 · PM5 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.178. BayesDel score = -0.147545.
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
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.
Sources & reference links