Classification rationale

PM2 BP4 VUS

KMT2A c.5518C>T

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.¹ 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.² 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 -0.184716.³ This variant has not been shown to lie in a statistically significant hotspot.⁴

PM2 + BP4 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗revelbayesdel

4 hotspots ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

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

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PM2 moderate Pathogenic

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 v2.1 AF 3.19053e-05 (8/250742).gnomAD v4.1 AF 2.60279e-05 (42/1613654).Highest subpopulation AF 0.000743595 in Ashkenazi Jewish samples.

gnomad_v2 ↗gnomad_v4 ↗

BP4 supporting Benign

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 max delta score 0.02.REVEL score 0.326.BayesDel score -0.184716.

spliceai ↗

Assessed · not applied · 6 not met · 12 not assessed

Pathogenic

PS1 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.

PS2 No confirmed de novo occurrence with maternity and paternity established was identified for this variant.

PS3 No published well-established functional study was identified showing a damaging effect of this specific KMT2A variant.

PS4 No case series, case-control enrichment study, or multiple independent affected observations were identified to show that this variant is enriched in affected individuals.

PM1 This variant has not been shown to lie in a mutational hotspot or a well-established critical functional region without benign variation.

PM6 No assumed de novo occurrence without full parental confirmation was identified for this variant.

PP1 No segregation data were identified for this variant.

PP2 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.

PP3 Available computational evidence does not support a damaging effect.

PP4 No phenotype description or clinical specificity data were provided to determine whether the observed phenotype is highly specific for a KMT2A-related disorder.

Benign

BA1 Population frequency does not meet the benign stand-alone threshold.

BS1 Population frequency does not exceed the benign strong threshold.

BS2 Available population data do not provide established observations of this variant in clearly unaffected individuals sufficient for BS2.

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

BS4 No family study was identified showing lack of segregation of this variant with disease.

BP1 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.

BP2 No phase information was identified to determine whether this variant occurs in trans with a pathogenic variant or in cis with another variant.

BP5 No independent alternate molecular diagnosis or alternate cause for disease was provided for assessment of BP5.

N/A · 8 PVS1 · PM3 · PM4 · PM5 · PP5 · BP3 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 2.60279e-05; MAF= 0.00260%, 42/1613654 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000743595; MAF= 0.07436%, 22/29586 alleles, homozygotes = 0); grpmax FAF= 5.42e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.19053e-05; MAF= 0.00319%, 8/250742 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000398645; MAF= 0.03986%, 4/10034 alleles, homozygotes = 0); grpmax FAF= 2.93e-06.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0026% · 42 / 1,613,654
0 hom · FAF 0.00054%

Ashkenazi Jewish 22 / 29,586	0.074%
Remaining individuals 8 / 62,470	0.013%
European (non-Finnish) 12 / 1,179,880	0.001%

+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, African/African American)

gnomAD v2.1

0.0032% · 8 / 250,742
0 hom · FAF 0.00029%

Ashkenazi Jewish 4 / 10,034	0.04%
Remaining individuals 2 / 6,110	0.033%
European (non-Finnish) 2 / 113,370	0.0018%

+ 5 not observed (African/African American, Admixed American, East Asian, European (Finnish), South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (2 clinical laboratories). (ClinVarID = 2165272)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.326. BayesDel score = -0.184716.

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

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 12 PMIDs not cited in assessment

23619275 ↗ ACMG position statement on prenatal/preconception expanded carrier screening. CLINVAR

23652378 ↗ A framework to start the debate on neonatal screening policies in the EU: an Expert Opinion Document. CLINVAR

25626707 ↗ Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes. CLINVAR

25730230 ↗ Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine. CLINVAR

23169492 ↗ The perspective from EASAC and FEAM on direct-to-consumer genetic testing for health-related purposes. CLINVAR

24121147 ↗ Appropriateness of newborn screening for α1-antitrypsin deficiency. CLINVAR

22947299 ↗ Specific guidelines for assessing and improving the methodological quality of economic evaluations of newborn screening. CLINVAR

23037933 ↗ Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children. CLINVAR

23881473 ↗ Newborn screening: education, consent, and the residual blood spot. The position of the national society of genetic counselors. CLINVAR

24022298 ↗ Offering prenatal diagnostic tests: European guidelines for clinical practice [corrected]. CLINVAR

24394680 ↗ Parental permission for pilot newborn screening research: guidelines from the NBSTRN. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

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