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 ↗

Gene diagram · NM_005933.3 · variants mapped to exon structure

KMT2A NM_005933.3

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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