chr15-66435117-G-C

Variant names:

• chr15-66435117-G-C
• rs869025608
• NM_002755.4:c.171G>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_002755.4(MAP2K1):​c.171G>C​(p.Lys57Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP2K1 NM_002755.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.54

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 Uncertain_significance. Variant got 5 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, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K1	NM_002755.4	c.171G>C	p.Lys57Asn	missense_variant	Exon 2 of 11	ENST00000307102.10	NP_002746.1
MAP2K1	NM_001411065.1	c.105G>C	p.Lys35Asn	missense_variant	Exon 2 of 10		NP_001397994.1
MAP2K1	XM_011521783.4	c.105G>C	p.Lys35Asn	missense_variant	Exon 2 of 11		XP_011520085.1
MAP2K1	XM_017022411.3	c.171G>C	p.Lys57Asn	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.171G>C	p.Lys57Asn	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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arteriovenous malformation Pathogenic:1

Nov 25, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A MAP2K1 c.171G>C (p.Lys57Asn) variant was identified at an allelic fraction consistent with somatic origin. This same amino acid change (p.Lys57Asn) due to a different nucleotide change (c.171G>T) has been reported in multiple individuals with arteriovenous malformations (Couto JA et al., PMID: 28190454; Maurus K et al., PMID: 34726260; Schmidt VF et al., PMID: 38563363; Zenner K et al., PMID: 32884133). The MAP2K1 c.171G>C (p.Lys57Asn) variant has also been identified in numerous cases in the cancer database COSMIC (Genomic Mutation ID: COSV61070413). It is absent from the general population (gnomAD v.4.1.0), indicating it is not a common variant. It resides within the negative regulatory region of the MEK1 protein that is defined as a critical functional domain (Waterfall JJ et al., PMID: 24241536) and where pathogenic variants are known to cluster (Dentici ML et al., PMID: 19156172). Another variant in the same codon, c.169A>C (p.Lys57Gln), has been reported in affected individuals and is considered likely pathogenic (ClinVar ID: 40779). Functional studies show that the MAP2K1 (p.Lys57Asn) variant confers a gain of function to MEK1 as demonstrated by increased autophosphorylation and phosphorylation of downstream ERK and ribosomal protein S6 kinase (RSK), leading to increased cell viability, proliferation, and transformation, as well as resistance to some MEK and BRAF inhibitors (Marks JL et al., PMID: 18632602; Kinoshita-Kikuta E et al., PMID: 29753091; Grisham RN et al., PMID: 26324360; Ng PKS et al., PMID: 29533785; Arcila ME et al., PMID: 25351745; Mizuno S et al., PMID: 36442478). The MAP2K1 gene is defined by the ClinGen RASopathy expert panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (Gelb BD, et al., PMID: 29493581). 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), the MAP2K1 c.171G>C (p.Lys57Asn) variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.7	M
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.040	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.36		Loss of ubiquitination at K57 (P = 0.0027);
MVP		0.96
MPC		2.7
ClinPred		0.99	D
GERP RS		1.7
Varity_R		0.94
gMVP		0.94

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: rs869025608; hg19: chr15-66727455; COSMIC: COSV61070413;