19-4101105-C-T

Position:

• chr19-4101105-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS4 PS2 PM2 PM6 PP2

This summary comes from the ClinGen Evidence Repository: The c.619G>A (p.Glu207Lys) variant in MAP2K2 was absent from large population studies (PM2; gnomAD.broadinstitute.org). It has been identified in 6 individuals with clinical features of a RASopathy (PS4; SCV000204213.4, SCV000207959.10, SCV000815593.1, Otto von Guericke University Magdeburg internal data). One of these cases was a confirmed de novo occurrence and another was an unconfirmed de novo occurrence (PS2; PM6; SCV000815593.1, Otto von Guericke University Magdeburg internal data). Additionally, the c.619G>A (p.Glu207Lys) is located in MAP2K2, 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 pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4, PS2, PM6, PM2, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA180944/MONDO:0015280/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP2K2 NM_030662.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:8 O:1
• Conservation: PhyloP100: 7.86

Genes affected

MAP2K2 (HGNC:6842): (mitogen-activated protein kinase kinase 2) The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This kinase is known to play a critical role in mitogen growth factor signal transduction. It phosphorylates and thus activates MAPK1/ERK2 and MAPK2/ERK3. The activation of this kinase itself is dependent on the Ser/Thr phosphorylation by MAP kinase kinase kinases. Mutations in this gene cause cardiofaciocutaneous syndrome (CFC syndrome), a disease characterized by heart defects, cognitive disability, and distinctive facial features similar to those found in Noonan syndrome. The inhibition or degradation of this kinase is also found to be involved in the pathogenesis of Yersinia and anthrax. A pseudogene, which is located on chromosome 7, has been identified for this gene. [provided by RefSeq, Jul 2008]

MAP2K2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 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.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP2K2	NM_030662.4	c.619G>A	p.Glu207Lys	missense_variant	6/11	ENST00000262948.10	NP_109587.1
MAP2K2	XM_006722799.3	c.619G>A	p.Glu207Lys	missense_variant	6/9		XP_006722862.1
MAP2K2	XM_047439100.1	c.49G>A	p.Glu17Lys	missense_variant	4/9		XP_047295056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10	c.619G>A	p.Glu207Lys	missense_variant	6/11	1	NM_030662.4	ENSP00000262948.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 53

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	May 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2021	Reported as a somatic variant identified in malignant melanomas (Nikolaev et al., 2012); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 24055054, 22197931, 27301426) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	MAP2K2: PM2, PM5, PS4:Moderate, PM6:Supporting -

Cardio-facio-cutaneous syndrome Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	May 09, 2017	The c.619G>A (p.Glu207Lys) variant in MAP2K2 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; LMM GeneDx internal data; GTR ID's 21766, 26957; SCV000207959.10, SCV000204213.4). The p.Glu207Lys variant has been identified in 2 independent occurrences in patients with a RASopathy (PS4_Supporting; LMM GeneDx internal data; GTR ID's 21766, 26957; SCV000207959.10, SCV000204213.4). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Glu207Lys variant may impact the protein (PP3). The variant is located in the MAP2K2 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_Strong, PS4_Supporting, PM2, PP3, PP2. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 24, 2021	Variant summary: MAP2K2 c.619G>A (p.Glu207Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 236530 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.619G>A has been reported in the literature in at least an individual affected with Cardiofaciocutaneous Syndrome (Lallar_2020). Additionally, several reportedly de novo occurrences have been mentioned in ClinVar (SCV000815593.1, SCV000207959.10, SCV000204213.4). Four ClinVar submitters (evaluation after 2014) including an expert panel (ClinGen RASopathy Variant Curation Expert Panel) cite the variant as Pathogenic (n=2) or likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

RASopathy Pathogenic:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 12, 2022	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 207 of the MAP2K2 protein (p.Glu207Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of MAP2K2-related conditions (PMID: 33452774; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40813). 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 expected to disrupt MAP2K2 protein function. -

Noonan syndrome;C1275081:Cardio-facio-cutaneous syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 23, 2013

The Glu207Lys variant in MAP2K2 has been identified by our laboratory in 2 indiv iduals with clinical features of Noonan syndrome and Cardio-facio-cutaneous synd rome. This variant was found to have occurred de novo in one proband (LMM unpubl ished data). In addition, this variant is absent in large population studies. Co mputational analyses (biochemical amino acid properties, conservation, AlignGVGD , PolyPhen2, and SIFT) suggest that the Glu207Lys variant may impact the protein . In summary, this variant is likely pathogenic, though additional studies are r equired to fully establish its clinical significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.89	L;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.031	D;T
Polyphen		1.0	D;.
Vest4		0.85
MutPred		0.68		Gain of MoRF binding (P = 0.0092);.;
MVP		0.82
MPC		1.2
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.76
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs727504382; hg19: chr19-4101103; COSMIC: COSV53562848; COSMIC: COSV53562848;