NM_001197104.2(KMT2A):c.7255G>A (p.Glu2419Lys) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Oct 13, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001571496.18

Allele description [Variation Report for NM_001197104.2(KMT2A):c.7255G>A (p.Glu2419Lys)]

NM_001197104.2(KMT2A):c.7255G>A (p.Glu2419Lys)

Gene:

KMT2A:lysine methyltransferase 2A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q23.3

Genomic location:

Preferred name:

NM_001197104.2(KMT2A):c.7255G>A (p.Glu2419Lys)

HGVS:

NC_000011.10:g.118503147G>A
NG_027813.1:g.71658G>A
NM_001197104.2:c.7255G>AMANE SELECT
NM_005933.4:c.7246G>A
NP_001184033.1:p.Glu2419Lys
NP_005924.2:p.Glu2416Lys
LRG_613t1:c.7255G>A
LRG_613:g.71658G>A
NC_000011.9:g.118373862G>A
NM_001197104.1:c.7255G>A

Protein change:

E2416K

Links:

dbSNP: rs782181274

NCBI 1000 Genomes Browser:

rs782181274

Molecular consequence:

NM_001197104.2:c.7255G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005933.4:c.7246G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001795981	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Oct 28, 2020)	germline	clinical testing	Citation Link,
SCV002215053	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 13, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29203834, 28492532
SCV004129402	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Benign (Oct 1, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001795981

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely benign
(Oct 28, 2020)

germline

clinical testing

Citation Link,

SCV002215053

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 13, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004129402

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Benign
(Oct 1, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular and cellular issues of KMT2A variants involved in Wiedemann-Steiner syndrome.

Lebrun N, Giurgea I, Goldenberg A, Dieux A, Afenjar A, Ghoumid J, Diebold B, Mietton L, Briand-Suleau A, Billuart P, Bienvenu T.

Eur J Hum Genet. 2018 Jan;26(1):107-116. doi: 10.1038/s41431-017-0033-y. Epub 2017 Dec 4.

PubMed [citation]

PMID:: 29203834
PMCID:: PMC5839021

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

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From GeneDx, SCV001795981.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002215053.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2419 of the KMT2A protein (p.Glu2419Lys). This variant is present in population databases (rs782181274, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of KMT2A-related conditions (PMID: 29203834). ClinVar contains an entry for this variant (Variation ID: 1204982). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KMT2A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV004129402.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	not provided

Description

KMT2A: BP4, BS1, BS2

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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