About KMT2A
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
KMT2A c.5518C>T, p.(Pro1840Ser)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate
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.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
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.
Recorded classification: Uncertain significance
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 moderate, BP4 supporting; combination = 1 moderate + 1 supporting benign, which maps to VUS because the evidence is conflicting.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
42 / 1,613,654 alleles
gnomAD v4.1: 42 / 1,613,654 alleles. Recorded AF 2.60279e-05. Recorded homozygote count 0.
gnomAD 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.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
2 reported laboratory submissions
2 Likely benign.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 6 not met · 12 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
This variant has not been shown to lie in a statistically significant hotspot.
No criteria match.
Met · 2
PM2 ModerateThis 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. Details ▾Hide ▴
Rule
Generic ACMG population threshold fallback (PM2 <0.1%)
Evidence considered
- 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.
Sources
BP4 SupportingMultiple 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. Details ▾Hide ▴
Rule
ACMG/AMP BP4
Evidence considered
- SpliceAI max delta score 0.02.
- REVEL score 0.326.
- BayesDel score -0.184716.
Sources
Not met · 6 · evaluated, threshold not reached
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. Details ▾Hide ▴
Rule
ACMG/AMP PS1
Evidence considered
- ClinVar record reviewed for the exact variant.
Still missing
- A validated pathogenic same-amino-acid comparator was not identified.
Sources
PM1 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. Details ▾Hide ▴
Rule
ACMG/AMP PM1
Evidence considered
- No hotspot row was found for KMT2A residue P1840.
Still missing
- No disease-specific missense clustering evidence for this residue or immediate region was identified.
Sources
PP3 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. Details ▾Hide ▴
Rule
ACMG/AMP PP3
Evidence considered
- SpliceAI max delta score 0.02.
- REVEL score 0.326.
- BayesDel score -0.184716.
Sources
BA1 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. Details ▾Hide ▴
Rule
Generic ACMG population threshold fallback (BA1 >1%)
Evidence considered
- Highest subpopulation AF 0.000743595 in gnomAD v4.1.
Sources
BS1 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. Details ▾Hide ▴
Rule
Generic ACMG population threshold fallback (BS1 >0.3%)
Evidence considered
- Highest subpopulation AF 0.000743595 in gnomAD v4.1.
Sources
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. Details ▾Hide ▴
Rule
ACMG/AMP BP1
Evidence considered
- Gene-level disease mechanism is not restricted to truncating variants alone.
Sources
pvs1_gene_context
Not assessed · 12 · no assessment recorded
PS2 No confirmed de novo occurrence with maternity and paternity established was identified for this variant. Details ▾Hide ▴
Rule
ACMG/AMP PS2
Evidence considered
- ClinVar review did not provide confirmed de novo data.
Still missing
- No trio-based case report or submitter record documenting confirmed de novo status was identified.
Sources
PS3 No published well-established functional study was identified showing a damaging effect of this specific KMT2A variant. Details ▾Hide ▴
Rule
ACMG/AMP PS3
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence.
Still missing
- No variant-specific functional assay was identified.
Sources
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. Details ▾Hide ▴
Rule
ACMG/AMP PS4
Evidence considered
- Single ClinVar aggregation reviewed.
- Population frequencies were available for comparison.
Still missing
- No exact-variant affected case count was identified.
- No case-control enrichment data were identified.
Sources
PM6 No assumed de novo occurrence without full parental confirmation was identified for this variant. Details ▾Hide ▴
Rule
ACMG/AMP PM6
Evidence considered
- ClinVar review did not provide assumed de novo data.
Still missing
- No case report or database submission describing de novo occurrence without confirmed parentage was identified.
Sources
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Rule
ACMG/AMP PP1
Evidence considered
- ClinVar review did not provide segregation data.
Still missing
- No informative family segregation study was identified.
Sources
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. Details ▾Hide ▴
Rule
ACMG/AMP PP2
Evidence considered
- Gene-level review emphasized loss of function rather than a PP2-specific missense framework.
Still missing
- No gene-level missense mechanism analysis supporting PP2 was identified.
Sources
pvs1_gene_context
PP4 No phenotype description or clinical specificity data were provided to determine whether the observed phenotype is highly specific for a KMT2A-related disorder. Details ▾Hide ▴
Rule
ACMG/AMP PP4
Still missing
- Phenotype and clinical correlation data were not available for review.
BS2 Available population data do not provide established observations of this variant in clearly unaffected individuals sufficient for BS2. Details ▾Hide ▴
Rule
ACMG/AMP BS2
Evidence considered
- Population databases show heterozygous observations but no qualifying unaffected-carrier evidence for BS2.
Still missing
- No unaffected carrier dataset or disease-specific penetrance context supporting BS2 was identified.
Sources
BS3 No well-established functional study was identified showing normal function for this specific variant. Details ▾Hide ▴
Rule
ACMG/AMP BS3
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence.
Still missing
- No variant-specific benign functional assay was identified.
Sources
BS4 No family study was identified showing lack of segregation of this variant with disease. Details ▾Hide ▴
Rule
ACMG/AMP BS4
Evidence considered
- ClinVar review did not provide non-segregation data.
Still missing
- No informative non-segregation evidence was identified.
Sources
BP2 No phase information was identified to determine whether this variant occurs in trans with a pathogenic variant or in cis with another variant. Details ▾Hide ▴
Rule
ACMG/AMP BP2
Still missing
- No phasing data were identified.
BP5 No independent alternate molecular diagnosis or alternate cause for disease was provided for assessment of BP5. Details ▾Hide ▴
Rule
ACMG/AMP BP5
Still missing
- No alternate molecular explanation data were available.
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ALoss 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. Details ▾Hide ▴
Rule
Generic ACMG/AMP PVS1 with ClinGen SVI generic PVS1 fallback
Evidence considered
- KMT2A loss of function is supported at the gene level.
- NM_005933.3:c.5518C>T is a missense variant outside the default generic PVS1 buckets.
Sources
PM3 N/APM3 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. Details ▾Hide ▴
Rule
ACMG/AMP PM3
Evidence considered
- Generic ACMG framework in a non-recessive context.
Sources
final_classification_framework
PM4 N/AThis is a missense substitution and does not cause a protein length change from an in-frame insertion/deletion or stop-loss event. Details ▾Hide ▴
Rule
ACMG/AMP PM4
Evidence considered
- Variant consequence is missense.
PM5 N/AA 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. Details ▾Hide ▴
Rule
ACMG/AMP PM5
Evidence considered
- PM5 candidate review found no eligible comparator variants and could not confirm classic PM5 semantics.
Still missing
- No validated pathogenic or likely pathogenic same-residue comparator was identified.
Sources
pm5_candidates
PP5 N/AA reputable-source-only pathogenic criterion was not used. Current review relied on the underlying available evidence rather than applying PP5. Details ▾Hide ▴
Rule
ACMG/AMP PP5
Evidence considered
- ClinVar submission exists
- but PP5 was not used as standalone evidence.
Sources
BP3 N/AThis criterion applies to in-frame deletions or insertions in repetitive regions without known function. It does not apply to this missense substitution. Details ▾Hide ▴
Rule
ACMG/AMP BP3
Evidence considered
- Variant consequence is missense.
BP6 N/AA reputable-source-only benign criterion was not used. Although ClinVar lists this variant as likely benign, BP6 was not applied as standalone evidence. Details ▾Hide ▴
Rule
ACMG/AMP BP6
Evidence considered
- ClinVar reports likely benign classification from two clinical laboratories
- without expert panel review.
Sources
BP7 N/ABP7 applies to synonymous or certain noncoding variants with no predicted splice impact. This variant is missense, so BP7 does not apply. Details ▾Hide ▴
Rule
ACMG/AMP BP7
Evidence considered
- Variant consequence is missense
- SpliceAI showed no significant splice impact but BP7 is not a missense criterion.
Sources
Identifiers
- Gene
- KMT2A
- Transcript
- NM_005933.3
- Coding (HGVS c.)
- NM_005933.3:c.5518C>T
- Protein (HGVS p.)
- NP_005924.2:p.(Pro1840Ser)
- GRCh38
- chr11:118495863 C>T
- GRCh37
- chr11:118366578 C>T
- ClinVar
- 2165272
Gene diagram
Every interpreted variant in KMT2A, mapped onto the exon structure of NM_005933.3. Select a row to find it on the plot.
KMT2ANM_005933.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in KMT2A
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
42 / 1,613,654 alleles
AF 2.6e-05 · 0 homozygotes · FAF 5.42e-06
gnomAD v2.1
8 / 250,742 alleles
AF 3.19e-05 · 0 homozygotes · FAF 2.93e-06
By genetic ancestry
gnomAD v4.1
AF 2.6e-05 · 42 / 1,613,654 alleles · 0 hom · FAF 5.4e-06
| Ashkenazi Jewish22 / 29,586 | 0.00074 |
| Remaining individuals8 / 62,470 | 0.00013 |
| European (non-Finnish)12 / 1,179,880 | 1e-05 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, African/African American.
gnomAD v2.1
AF 3.2e-05 · 8 / 250,742 alleles · 0 hom · FAF 2.9e-06
| Ashkenazi Jewish4 / 10,034 | 0.0004 |
| Remaining individuals2 / 6,110 | 0.00033 |
| European (non-Finnish)2 / 113,370 | 1.8e-05 |
0 alternate alleles recorded in 5 other groups: African/African American, Admixed American, East Asian, European (Finnish), South Asian.
Statements
gnomAD 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.
gnomAD 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.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.326
- BayesDel
- -0.185
How the predictions were used
BP4 SupportingMultiple 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. Details ▾Hide ▴
Rule
ACMG/AMP BP4
Evidence considered
- SpliceAI max delta score 0.02.
- REVEL score 0.326.
- BayesDel score -0.184716.
Sources
PP3 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. Details ▾Hide ▴
Rule
ACMG/AMP PP3
Evidence considered
- SpliceAI max delta score 0.02.
- REVEL score 0.326.
- BayesDel score -0.184716.
Sources
BP7 N/ABP7 applies to synonymous or certain noncoding variants with no predicted splice impact. This variant is missense, so BP7 does not apply. Details ▾Hide ▴
Rule
ACMG/AMP BP7
Evidence considered
- Variant consequence is missense
- SpliceAI showed no significant splice impact but BP7 is not a missense criterion.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.326. BayesDel score = -0.184716.
12 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 23619275 ↗ACMG position statement on prenatal/preconception expanded carrier screening.No paper-specific finding is recorded.
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PMID 23652378 ↗A framework to start the debate on neonatal screening policies in the EU: an Expert Opinion Document.No paper-specific finding is recorded.
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PMID 25626707 ↗Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes.Howard HC et al. · 2015No paper-specific finding is recorded.
-
PMID 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.No paper-specific finding is recorded.
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PMID 23169492 ↗The perspective from EASAC and FEAM on direct-to-consumer genetic testing for health-related purposes.Fears R et al. · 2013No paper-specific finding is recorded.
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PMID 24121147 ↗Appropriateness of newborn screening for α1-antitrypsin deficiency.Teckman J et al. · 2014No paper-specific finding is recorded.
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PMID 22947299 ↗Specific guidelines for assessing and improving the methodological quality of economic evaluations of newborn screening.Langer A et al. · 2012No paper-specific finding is recorded.
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PMID 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.Therrell BL et al. · 2013No paper-specific finding is recorded.
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PMID 23881473 ↗Newborn screening: education, consent, and the residual blood spot. The position of the national society of genetic counselors.No paper-specific finding is recorded.
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PMID 24022298 ↗Offering prenatal diagnostic tests: European guidelines for clinical practice [corrected].No paper-specific finding is recorded.
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PMID 24394680 ↗Parental permission for pilot newborn screening research: guidelines from the NBSTRN.No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
42 / 1,613,654 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
Open source ↗
ClinVar
2 Likely benign
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/2165272/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-118366578-C-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-118495863-C-T?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005933.3%3Ac.5518…
- OncoKB ↗www.oncokb.org/gene/KMT2A/P1840S
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=KMT2A+c.5518C%3ET
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD 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.
gnomAD 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.
ClinVar
This variant has been reported in ClinVar as Likely benign (2 clinical laboratories). (ClinVarID = 2165272)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.326. BayesDel score = -0.184716.
Functional
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
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.