Variant classification summary

NM_005933.3:c.2684A>G

KMT2A · NP_005924.2:p.(Lys895Arg) · NM_005933.3

GRCh37: chr11:118344558 A>G · GRCh38: chr11:118473843 A>G

Gene: KMT2A Transcript: NM_005933.3

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

KMT2A

Transcript

NM_005933.3

Protein

NP_005924.2:p.(Lys895Arg)

gnomAD AF

4.151022886385884e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_005933.3:c.2684A>G (p.Lys895Arg) is a missense variant in exon 3 of KMT2A, a gene associated with autosomal dominant Wiedemann-Steiner syndrome.

2

This variant is extremely rare in large population databases, with an allele frequency of 0.00283% in gnomAD v2.1 (8/282,230 alleles) and 0.00415% in gnomAD v4.1 (67/1,614,060 alleles), with no homozygotes observed. It is absent from gnomAD-Canada (PM2_Supporting).

3

Multiple lines of computational evidence predict a benign effect: REVEL score 0.224 (benign range), BayesDel score -0.154507 (benign), and SpliceAI predicts no splicing impact with a maximum delta score of 0.02 (BP4_Supporting).

4

This variant has been reported in ClinVar (Variation ID 1335086) with conflicting classifications: Uncertain significance by Invitae and Likely benign by CeGaT Center for Human Genetics Tuebingen. Neither submission reaches a definitive pathogenic or benign classification.

5

The only publication associated with ClinVar submissions (PMID 28492532, Sherloc classification framework) does not mention this specific variant; it was reviewed in full text and confirmed to be a methodology reference only.

6

This variant has been reported in COSMIC (COSV63290798) in 4 somatic cancer samples, but this does not constitute germline disease evidence.

7

Several potentially relevant publications were identified by exploratory literature search (de novo report, functional studies, cosegregation data, domain hotspot analysis) but none of the associated PMIDs are present in the case directory for verification; these criteria (PS2, PS3, PS4, PM1, PM6, PP1, BS3) remain not assessed pending full-text retrieval and verification.

8

Applying the generic ACMG/AMP 2015 combination rules (PMID 25741868): the criteria met are PM2_Supporting (pathogenic) and BP4_Supporting (benign). These are conflicting at the supporting level and are insufficient to reach a likely pathogenic or likely benign classification. The variant is classified as a Variant of Uncertain Significance (VUS).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of 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	This is a missense variant (c.2684A>G, p.Lys895Arg) and does not fall into any null-variant bucket (nonsense, frameshift, canonical ±1,2 splice consensus, initiation codon, or exon-level deletion). The pvs1_variant_assessment confirms variant_bucket='other' and apply_generic_pvs1_framework=false.	pvs1_variant_assessment pvs1_gene_context
PS1	Not assessed	No evidence of a different nucleotide change at codon 895 previously established as pathogenic. PS1 requires a known pathogenic variant at the same amino acid position resulting from a different nucleotide substitution.
PS2	Not assessed	Exploratory literature search returned a lead suggesting a de novo occurrence of this variant in a child with Wiedemann-Steiner syndrome (PMID 35123456), but this PMID is not present in the case publications directory and the full text cannot be verified. Without confirming the variant is mentioned in the source and that parentage was confirmed, PS2 cannot be applied.
PS3	Not assessed	Exploratory literature search returned a lead suggesting reduced H3K4 methyltransferase activity (~35% of wild-type) for p.Lys895Arg (PMID 34210987), and a conflicting study suggesting normal activity (PMID 34567890). Neither PMID is present in the case publications directory, and the claims cannot be verified. COSMIC reports 4 somatic occurrences but this does not constitute well-established functional evidence for germline pathogenicity.
PS4	Not assessed	The variant prevalence in affected individuals versus the general population cannot be reliably determined from available data. ClinVar has only 2 submitters (Invitae: VUS; CeGaT: LB) and no proband counts are specified. An exploratory lead claimed 5 unrelated probands but the source cannot be verified. The gnomAD population frequency is extremely low (AF ~0.003-0.004%), which would support case-control comparison if affected counts were known.	clinvar gnomad_v2 gnomad_v4
PS5	Not assessed	No evidence from a reputable source recently reporting this variant as pathogenic. The ClinVar submissions are VUS (Invitae) and Likely benign (CeGaT). No expert panel or guideline-based classification calling this variant pathogenic is available.	clinvar
PM1	Not assessed	Exploratory literature search suggested residue 895 lies within the PHD1 finger domain (residues 880-940), a known functional domain in KMT2A with enrichment of pathogenic missense variants (PMID 32165498). However, the cited PMID is not in the case publications directory and the domain hotspot status cannot be verified from available sources. The cancer hotspots analysis classified the residue as not statistically significant for somatic mutations, but this does not directly address germline domain-level constraint.
PM2	Met	The variant is extremely rare in large population databases. gnomAD v2.1 reports an allele frequency of 0.00283% (8/282,230 alleles; 0 homozygotes; grpmax FAF=2.867e-05) and gnomAD v4.1 reports 0.00415% (67/1,614,060 alleles; 0 homozygotes; grpmax FAF=4.264e-05). Both frequencies are well below the 0.1% threshold for PM2 under generic ACMG/AMP. The variant is absent from gnomAD-Canada.	gnomad_v2 gnomad_v4
PM5	N/A	No pathogenic comparator variant at the same amino acid residue (Lys895) with a different amino acid change could be identified. The pm5_candidates.json returned no candidates and recommended against applying PM5.	pm5_candidates
PM6	Not assessed	Exploratory literature search returned a lead describing a de novo occurrence without confirmed parentage (PMID 35123456). This PMID is not present in the case publications directory and cannot be verified. Without a verified de novo observation, PM6 cannot be applied.
PP1	Not assessed	Exploratory literature search returned a lead describing cosegregation of this variant with Wiedemann-Steiner syndrome in a family (3 meioses; PMID 32876543). This PMID is not present in the case publications directory and cannot be verified. Without confirmed cosegregation data, PP1 cannot be applied.
PP2	Not assessed	PP2 requires that the gene has a low rate of benign missense variation (high constraint) and that missense variants are a common disease mechanism. While KMT2A missense variants are a recognized cause of Wiedemann-Steiner syndrome, specific constraint metrics (e.g., missense Z-score, gnomAD o/e ratio) were not available in the evidence bundle for this gene. Cannot apply without these quantitative data.
PP3	Not met	Multiple in silico tools predict a benign effect for this variant. REVEL score is 0.224 (well below the typical 0.5 threshold for pathogenic prediction). BayesDel score is -0.154507 (negative scores indicate benign). SpliceAI predicts no significant splice impact (max delta score = 0.02). None of the computational predictors support a damaging effect.	revel bayesdel spliceai
PP4	Not assessed	No detailed patient phenotype data are available in verifiable sources. The ClinVar submissions do not include condition labels or phenotype descriptions. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5	Not met	No reputable source has recently reported this variant as pathogenic. The ClinVar record (1335086) shows classifications of Uncertain significance (Invitae) and Likely benign (CeGaT). The only associated publication (PMID 28492532) is a methodology paper (Sherloc classification framework) that does not mention this specific variant — it was cited by Invitae as a general classification reference. Full-text review confirmed the variant is not discussed.	clinvar PMID:28492532
BA1	Not met	The variant is extremely rare in population databases, far below the 1% BA1 threshold. The highest observed subpopulation frequency is 0.01644% (Middle Eastern, gnomAD v4.1). The overall gnomAD v4.1 AF is 0.00415% and v2.1 AF is 0.00283%.	gnomad_v2 gnomad_v4
BS1	Not met	The variant frequency is far below the 0.3% BS1 threshold. The highest observed subpopulation frequency is 0.01644% (Middle Eastern, gnomAD v4.1). No population approaches the 0.3% threshold required for BS1.	gnomad_v2 gnomad_v4
BS2	Not assessed	No data available on observation of this variant in healthy adults without the associated phenotype. While gnomAD includes population controls, the disease (Wiedemann-Steiner syndrome) has variable expressivity and the health status of gnomAD individuals is unknown. BS2 requires confirmed observation in a healthy adult with full penetrance expected at an early age.
BS3	Not assessed	Exploratory literature search returned a lead describing a functional assay where p.Lys895Arg retained normal H3K4 methyltransferase activity in HEK293T cells (PMID 34567890), which would support BS3. However, this conflicts with another exploratory lead showing reduced activity (PMID 34210987). Neither PMID is in the case publications directory, and the claims cannot be verified.
BS4	Not assessed	No data available demonstrating lack of segregation of this variant with disease in affected family members. BS4 requires that the variant does not segregate with disease in families (e.g., an affected relative does not carry the variant). Available cosegregation data (unverifiable exploratory lead, PMID 32876543) actually suggests the variant does segregate with disease.
BP1	Not assessed	BP1 applies to missense variants in genes where primarily truncating variants cause disease. KMT2A-related Wiedemann-Steiner syndrome is caused by both missense and truncating variants. The pvs1_gene_context literature identifies both variant types as disease-causing. Without evidence that the gene's disease mechanism is exclusive to truncating variants, BP1 cannot be applied.	pvs1_gene_context
BP2	Not assessed	No data available on observation of this variant in trans with a known pathogenic KMT2A variant in an unaffected individual. KMT2A-related disease is autosomal dominant, making such observations unlikely. BP2 is generally not applicable to dominant conditions unless a specific recessive or digenic model is demonstrated.
BP4	Met	Multiple lines of computational evidence support a benign effect for this variant. REVEL predicts a benign score of 0.224 (threshold >0.5 for pathogenic). BayesDel predicts a benign score of -0.154507 (negative scores indicate benign). SpliceAI predicts no significant splice impact (max delta score = 0.02). All three independent in silico tools concordantly predict no damaging effect.	revel bayesdel spliceai
BP5	Not assessed	No data available on observation of this variant in a case with an alternate molecular basis for disease. BP5 requires that the variant is found in a patient with a clear alternate genetic cause for their phenotype.
BP6	Not met	No reputable source has reported this variant as definitively benign. While CeGaT Center for Human Genetics Tuebingen classified it as Likely benign (SCV002063013), and Invitae classified it as Uncertain significance (SCV002170738), neither classification reaches the 'benign' threshold required for BP6. A single Likely benign classification from a clinical laboratory, in the context of a conflicting VUS from another laboratory, does not meet the BP6 standard of a reputable source reporting the variant as benign.	clinvar
BP7	N/A	This is a missense variant (c.2684A>G, p.Lys895Arg), not a synonymous variant. BP7 applies only to synonymous (silent) variants with no predicted splice impact.

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