Variant classification summary

NM_005933.3:c.5518C>T

KMT2A · NP_005924.2:p.(Pro1840Ser) · NM_005933.3

GRCh37: chr11:118366578 C>T · GRCh38: chr11:118495863 C>T

Gene: KMT2A Transcript: NM_005933.3

Final call

VUS

PM2 moderate BP4 supporting

Variant details

Gene

KMT2A

Transcript

NM_005933.3

Protein

NP_005924.2:p.(Pro1840Ser)

gnomAD AF

2.602788454030418e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The KMT2A NM_005933.3:c.5518C>T (NP_005924.2:p.(Pro1840Ser)) variant has been reported in ClinVar as likely benign by two clinical laboratories, without expert panel review.

2

This variant is present in gnomAD v2.1 at 0.00319% (8/250,742 alleles) and in gnomAD v4.1 at 0.00260% (42/1,613,654 alleles), with highest observed Ashkenazi Jewish frequencies of 0.03986% and 0.07436%, respectively; these values are below the default 0.1% PM2 threshold and below the 0.3% BS1 threshold.

3

Computational evidence does not support a damaging effect: SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, REVEL is 0.326, and BayesDel is -0.184716.

4

This variant has not been shown to lie in a statistically significant hotspot.

Final determination: Generic ACMG/AMP 2015 fallback rules identified both pathogenic and benign evidence, so the overall classification remains Variant of Uncertain Significance because the evidence is conflicting.

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	Loss of function is an established germline disease mechanism for KMT2A, but this variant is a missense substitution in exon 19 and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice variants. Available evidence does not support applying PVS1 to this variant.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No evidence was identified that a different nucleotide change causing the same amino acid substitution has already been established as pathogenic or likely pathogenic for KMT2A.	clinvar
PS2	Not assessed	No confirmed de novo occurrence with maternity and paternity established was identified for this variant.	clinvar
PS3	Not assessed	No published well-established functional study was identified showing a damaging effect of this specific KMT2A variant.	oncokb
PS4	Not assessed	No case series, case-control enrichment study, or multiple independent affected observations were identified to show that this variant is enriched in affected individuals.	clinvar gnomad_v2 gnomad_v4
PM1	Not met	This variant has not been shown to lie in a mutational hotspot or a well-established critical functional region without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at this residue, and domain annotation alone is not sufficient for PM1.	hotspots
PM2	Met	This variant is rare in population databases. The highest observed population frequency is 0.07436% in gnomAD v4.1 Ashkenazi Jewish samples (22/29,586 alleles), which is below the default 0.1% PM2 threshold; overall frequencies are 0.00319% in gnomAD v2.1 and 0.00260% in gnomAD v4.1.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 is intended for recessive disorders with evidence of the variant in trans with a pathogenic variant. No recessive disease framework or trans observation applies here.	final_classification_framework
PM4	N/A	This is a missense substitution and does not cause a protein length change from an in-frame insertion/deletion or stop-loss event.
PM5	N/A	A same-residue pathogenic comparator supporting classic PM5 was not established. The available comparator review could not confirm that classic same-residue PM5 logic should be applied safely for this gene and variant.	pm5_candidates
PM6	Not assessed	No assumed de novo occurrence without full parental confirmation was identified for this variant.	clinvar
PP1	Not assessed	No segregation data were identified for this variant.	clinvar
PP2	Not assessed	Available evidence does not establish that KMT2A is a gene in which missense variation is a common mechanism of disease with a low rate of benign missense variation sufficient for PP2.	pvs1_gene_context
PP3	Not met	Available computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, REVEL is 0.326, and BayesDel is -0.184716.	spliceai revel bayesdel
PP4	Not assessed	No phenotype description or clinical specificity data were provided to determine whether the observed phenotype is highly specific for a KMT2A-related disorder.
PP5	N/A	A reputable-source-only pathogenic criterion was not used. Current review relied on the underlying available evidence rather than applying PP5.	clinvar
BA1	Not met	Population frequency does not meet the benign stand-alone threshold. The highest observed frequency is 0.07436% in gnomAD v4.1 Ashkenazi Jewish samples, which is below the default 1% BA1 threshold.	gnomad_v4
BS1	Not met	Population frequency does not exceed the benign strong threshold. The highest observed frequency is 0.07436% in gnomAD v4.1 Ashkenazi Jewish samples, which is below the default 0.3% BS1 threshold.	gnomad_v4
BS2	Not assessed	Available population data do not provide established observations of this variant in clearly unaffected individuals sufficient for BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study was identified showing normal function for this specific variant.	oncokb
BS4	Not assessed	No family study was identified showing lack of segregation of this variant with disease.	clinvar
BP1	Not met	BP1 was not applied because available gene-level evidence does not show that KMT2A disease is caused almost exclusively by truncating variants; missense variation is also reported in KMT2A-related disease.	pvs1_gene_context
BP2	Not assessed	No phase information was identified to determine whether this variant occurs in trans with a pathogenic variant or in cis with another variant.
BP3	N/A	This criterion applies to in-frame deletions or insertions in repetitive regions without known function. It does not apply to this missense substitution.
BP4	Met	Multiple computational data lines support no damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, REVEL is 0.326, and BayesDel is -0.184716, which together argue against a deleterious effect.	spliceai revel bayesdel
BP5	Not assessed	No independent alternate molecular diagnosis or alternate cause for disease was provided for assessment of BP5.
BP6	N/A	A reputable-source-only benign criterion was not used. Although ClinVar lists this variant as likely benign, BP6 was not applied as standalone evidence.	clinvar
BP7	N/A	BP7 applies to synonymous or certain noncoding variants with no predicted splice impact. This variant is missense, so BP7 does not apply.	spliceai

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