Variant classification summary

NM_005933.3:c.10244C>T

KMT2A · NP_005924.2:p.(Pro3415Leu) · NM_005933.3

GRCh37: chr11:118376860 C>T · GRCh38: chr11:118506145 C>T

Gene: KMT2A Transcript: NM_005933.3

Final call

VUS

PM2 supporting

Variant details

Gene

KMT2A

Transcript

NM_005933.3

Protein

NP_005924.2:p.(Pro3415Leu)

gnomAD AF

1.2390084463205785e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): absent from gnomAD v2.1 and gnomAD-Canada v1.0, with only 2 of 1,614,194 alleles in gnomAD v4.1 (AF 1.24e-06, zero homozygotes).

2

Under generic ACMG/AMP 2015 combination rules, a single supporting criterion does not reach the threshold for pathogenic or benign classification, so the variant remains VUS.

Final determination: 1 supporting criterion alone meets no combination threshold, so the variant is 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	Not applicable: PVS1 covers only null variants (nonsense, frameshift, canonical splice-site), and this is a missense substitution.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no ClinVar record of a different nucleotide substitution producing the same p.Pro3415Leu change has been classified pathogenic.	clinvar
PS2	Not assessed	Not assessed: no proband or parental genotypes document a confirmed de novo occurrence of p.Pro3415Leu.
PS3	Not assessed	Not assessed: no functional assay data (e.g., methyltransferase activity) for this variant were available.
PS4	Not assessed	Not assessed: no affected carriers of this variant or case-control enrichment data were documented.
PM1	Not assessed	Not assessed: no significant hotspot at residue 3415 was found, and its location relative to known KMT2A functional domains could not be confirmed.	oncokb
PM2	Met	Met (supporting): absent from gnomAD v2.1 and gnomAD-Canada, with only 2 of 1,614,194 alleles in gnomAD v4.1 (AF 1.24e-06, zero homozygotes).	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no evidence of this variant in trans with a pathogenic allele in an affected individual was available.
PM4	N/A	Not applicable: PM4 requires a protein-length change (in-frame indel or stop-loss), and this missense substitution does not alter length.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no pathogenic or likely pathogenic missense variant at residue 3415 with a different amino acid change was identified.	pm5_candidates
PM6	Not assessed	Not assessed: no de novo observation or parental-testing data are documented.
PP1	Not assessed	Not assessed: no relatives, genotypes, or informative meioses are reported, so cosegregation cannot be evaluated.
PP2	Not assessed	Not assessed: no missense constraint metric (e.g., gnomAD Z-score) was available to quantify benign missense tolerance in KMT2A.	pvs1_gene_context
PP3	Not met	Not met: REVEL 0.397 falls below the 0.644 PP3_Supporting threshold, and SpliceAI max delta 0.002 shows no splice impact.	revel bayesdel spliceai
PP4	Not assessed	Not assessed: no documented phenotype of a carrier establishes features highly specific for a KMT2A-related disorder.
PP5	Not met	Not met: the only ClinVar record is a single-laboratory uncertain-significance submission, not an expert-panel classification.	clinvar
BA1	Not met	Not met: gnomAD v4.1 allele frequency 1.24e-06 (2/1,614,194 alleles) is far below the >1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS1	Not met	Not met: the highest observed allele frequency (2.67e-05) does not exceed the expected maximum credible frequency for a rare dominant disorder.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: gnomAD v4.1 reports zero homozygotes, and no unaffected adult homozygous or hemizygous carriers are documented.	gnomad_v4
BS3	Not assessed	Not assessed: no functional assay data demonstrating normal (wild-type-like) function of p.Pro3415Leu were available.
BS4	Not assessed	Not assessed: no unaffected relatives tested negative are documented, so lack of segregation cannot be evaluated.
BP1	Not met	Not met: missense variants are a recognized, if less common, pathogenic mechanism in KMT2A, so missense cannot be excluded as disease-causing.	pvs1_gene_context
BP2	Not assessed	Not assessed: no phase-resolved data (in trans or in cis with a pathogenic variant) are available.
BP3	N/A	Not applicable: BP3 applies to in-frame indels in repetitive regions, and this missense substitution does not alter protein length.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.397 is above the 0.290 BP4_Supporting cutoff (indeterminate zone), and the negative SpliceAI signal alone is insufficient.	revel bayesdel spliceai
BP5	Not assessed	Not assessed: no affected carriers or credible alternative molecular explanation for a relevant phenotype are documented.
BP6	Not met	Not met: ClinVar holds only a single-laboratory uncertain-significance submission, with no expert-panel benign classification.	clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous (silent) variants, and this substitution changes the encoded amino acid.	generic_acmg_combination_rules

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