rs397516790

Variant names:

• chr15-66435115-A-C
• rs397516790
• NM_002755.4:c.169A>C

Your query was ambiguous. Multiple possible variants found:

• chr15-66435115-A-C
• chr15-66435115-A-G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS2 PS4 PM6 PM2 PM1 PP3 PP2

This summary comes from the ClinGen Evidence Repository: The c.169A>C variant in the MAP2K1 gene is a missense variant predicted to cause substitution of lysine by glutamine at amino acid 57 (p.Lys57Gln). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.726, evidence that the p.Lys57Gln variant may impact the protein function (PP3). The variant is located in the MAP2K1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2). The variant is located in a specific region supporting pathogenicity (PM1, aa 43-61). This variant has been reported in at least 6 independent patients with clinical feature of a RASopathy, 1 as a confirmed de novo occurrence and 1 as an unconfirmed de novo occurrence (PS2, PS4; Partners LMM, GeneDx, Invitae, Baylor, Otto von Guericke University Magdeburg internal data; ClinVar SCV000061249.5, SCV000207949.3, SCV001568953.4, PMID:35524774). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2, PS4, PM1, PM2_Supporting, PP2, PP3 (Specification Version 2.3, 12/3/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA134595/MONDO:0021060/045

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP2K1 NM_002755.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 9.19
• Publications: 55 publications found

Genes affected

MAP2K1 (HGNC:6840): (mitogen-activated protein kinase kinase 1) The protein encoded by this gene is a member of the dual specificity protein kinase family, which acts as a mitogen-activated protein (MAP) kinase kinase. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals. This protein kinase lies upstream of MAP kinases and stimulates the enzymatic activity of MAP kinases upon wide variety of extra- and intracellular signals. As an essential component of MAP kinase signal transduction pathway, this kinase is involved in many cellular processes such as proliferation, differentiation, transcription regulation and development. [provided by RefSeq, Jul 2008]

MAP2K1 Gene-Disease associations (from GenCC):

• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• cardiofaciocutaneous syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, ClinGen
• Noonan syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002755.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K1	NM_002755.4	MANE Select	c.169A>C	p.Lys57Gln	missense	Exon 2 of 11	NP_002746.1
	MAP2K1	NM_001411065.1		c.103A>C	p.Lys35Gln	missense	Exon 2 of 10	NP_001397994.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K1	ENST00000307102.10	TSL:1 MANE Select	c.169A>C	p.Lys57Gln	missense	Exon 2 of 11	ENSP00000302486.5
	MAP2K1	ENST00000685172.1		c.169A>C	p.Lys57Gln	missense	Exon 2 of 10	ENSP00000509604.1
	MAP2K1	ENST00000689951.1		c.169A>C	p.Lys57Gln	missense	Exon 2 of 12	ENSP00000509308.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

RASopathy Pathogenic:2 Uncertain:1

May 09, 2017

ClinGen RASopathy Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.169A>C (p.Lys57Gln) variant in MAP2K1 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; Partners LMM GeneDx internal data 26957, 21766; ClinVar SCV000061249.5; SCV000207949.2). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Lys57Gln variant may impact the protein (PP3). The variant is located in the MAP2K1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6, PM2, PP3, PP2.

Jun 24, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Experimental studies have shown that this missense change causes increased downstream phosphorylation of ERK (PMID: 18632602). This variant has not been reported in the literature in individuals with MAP2K1-related disease. ClinVar contains an entry for this variant (Variation ID: 40779). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with glutamine at codon 57 of the MAP2K1 protein (p.Lys57Gln). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamine.

Feb 14, 2019

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

To our knowledge, this variant has neither been published as a Pathogenic variant, nor has it been reported as a benign polymorphism. The K57Q missense change is considered to be a non-conservative amino acid substitution, as a positively charged residue (Lys) is replaced by a neutral residue (Gln) at a position in the protein that is highly conserved across species and within related proteins. Furthermore, missense changes in nearby codons (F53S and T55P) have previously been reported in association with cardio-facio-cutaneous syndrome and Costello syndrome, respectively, which are other disorders of the RAS/MAPK pathway (Rodriguez - Viciana et al., 2006; Nava et al., 2007). Therefore, K57Q is considered to be a likely pathogenic variant.

Cardio-facio-cutaneous syndrome Pathogenic:1

Feb 11, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		9.2
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.066	T
Polyphen		1.0	D
Vest4		0.57
MutPred		0.33		Loss of ubiquitination at K57 (P = 0.0027)
MVP		0.96
MPC		2.6
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.90
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397516790; hg19: chr15-66727453;