rs1057519729

chr15-66435113-A-Cchr15-66435113-A-Gchr15-66435113-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP2 PP3 PP5_Very_Strong

The NM_002755.4(MAP2K1):c.167A>C(p.Gln56Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP2K1 NM_002755.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.19

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_002755.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MAP2K1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839
• PP5: Variant 15-66435113-A-C is Pathogenic according to our data. Variant chr15-66435113-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 375978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP2K1	NM_002755.4	c.167A>C	p.Gln56Pro	missense_variant	2/11	ENST00000307102.10
MAP2K1	NM_001411065.1	c.101A>C	p.Gln34Pro	missense_variant	2/10
MAP2K1	XM_011521783.4	c.101A>C	p.Gln34Pro	missense_variant	2/11
MAP2K1	XM_017022411.3	c.167A>C	p.Gln56Pro	missense_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K1	ENST00000307102.10	c.167A>C	p.Gln56Pro	missense_variant	2/11	1	NM_002755.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Non-small cell lung carcinoma Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	Jul 14, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 24, 2011	The MEK1 Gln56Pro variant has been previously reported in a NSCLC cell line (Marks 2008). -

Melorheostosis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 23, 2020

- -

Melanoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Dec 26, 2014

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Jul 02, 2021

The c.167A>C (p.Gln56Pro) variant in MAP2K1 has been previously reported as a somatic finding in non-syndromic extracranial arteriovenous malformations (PMID: 28190454) and melorheostosis (PMID: 29643386). This variant overlaps those reported as oncogenic variants found in multiple tumor types (COSMIC and cBioPortal Databases). This variant has not been observed in large population studies (Genome Aggregation Database v2.1.1). The p.Gln56Pro variant is located at a highly-conserved site near the negative regulatory domain of the protein product (PMID: 29643386). Functional studies have demonstrated that the p.Gln56Pro substitution results in activation of downstream signaling (PMID: 25351745). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.013	D
Sift4G	Benign	0.11	T
Polyphen		0.70	P
Vest4		0.76
MutPred		0.28		Gain of glycosylation at Q56 (P = 0.0137);
MVP		0.99
MPC		2.2
ClinPred		0.98	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1057519729; hg19: chr15-66727451; COSMIC: COSV61068787;