rs1057519729

Variant names:

• chr15-66435113-A-C
• rs1057519729
• NM_002755.4:c.167A>C

Your query was ambiguous. Multiple possible variants found:

• chr15-66435113-A-C
• chr15-66435113-A-G
• chr15-66435113-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. 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:4 O:1
• 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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the MAP2K1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 35 curated benign missense variants. Gene score misZ: 3.1085 (above the threshold of 3.09). Trascript score misZ: 3.7499 (above the threshold of 3.09). GenCC associations: The gene is linked to Noonan syndrome with multiple lentigines, cardiofaciocutaneous syndrome 1, Noonan syndrome, cardiofaciocutaneous syndrome, cardiofaciocutaneous syndrome 3, Costello syndrome.
• 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 rank	MANE	Protein	UniProt
MAP2K1	NM_002755.4	c.167A>C	p.Gln56Pro	missense_variant	Exon 2 of 11	ENST00000307102.10	NP_002746.1
MAP2K1	NM_001411065.1	c.101A>C	p.Gln34Pro	missense_variant	Exon 2 of 10		NP_001397994.1
MAP2K1	XM_011521783.4	c.101A>C	p.Gln34Pro	missense_variant	Exon 2 of 11		XP_011520085.1
MAP2K1	XM_017022411.3	c.167A>C	p.Gln56Pro	missense_variant	Exon 2 of 10		XP_016877900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10	c.167A>C	p.Gln56Pro	missense_variant	Exon 2 of 11	1	NM_002755.4	ENSP00000302486.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Melorheostosis Pathogenic:1

Jun 23, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jul 02, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Non-small cell lung carcinoma Pathogenic:1

May 24, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MEK1 Gln56Pro variant has been previously reported in a NSCLC cell line (Marks 2008). -

Extracranial arteriovenous malformation Pathogenic:1

May 15, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A MAP2K1 c.167A>C (p.Gln56Pro) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in several individuals affected with non-syndromic extracranial arteriovenous malformations (Couto JA et al., PMID:28190454), melorheostosis (Kang H et al., PMID: 29643386), and in multiple tumor types (Marks JL et al., PMID:18632602, COSMIC database COSV61068787). It has been reported in the ClinVar database as pathogenic in a somatic state by a single clinical laboratory (ClinVar ID: 375978). This variant is absent from the general population (gnomAD v.4.1.0), indicating it is not a common variant. The MAP2K1 c.167A>C (p.Gln56Pro) variant resides within the negative regulatory domain of MAP2K1 at a critical mutational hot spot (Kang H et al., PMID:29643386). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to MAP2K1 function. In support of this prediction, functional studies have shown that MAP2K1 c.167A>C (p.Gln56Pro) induces ERK phosphorylation and cell proliferation, indicating that this variant impacts protein function (Kang H et al., PMID: 29643386, Arcila ME et al., PMID: 25351745). The MAP2K1 gene is defined by the ClinGen RASopathy expert panel (Gelb BD et al., PMID: 29493581) as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease. Based on available information and an internally developed protocol informed by the ACMG/AMP guidelines for variant interpretation and gene-specific practices from the ClinGen Criteria Specification Registry (Leon-Quintero FZ et al., PMID: 39434542), this variant is classified as pathogenic. -

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
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;