NM_002755.4(MAP2K1):c.848C>T (p.Ala283Val) AND not specified

Germline classification:: Likely benign (2 submissions)
Last evaluated:: Mar 23, 2020
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000037602.15

Allele description [Variation Report for NM_002755.4(MAP2K1):c.848C>T (p.Ala283Val)]

NM_002755.4(MAP2K1):c.848C>T (p.Ala283Val)

Gene:

MAP2K1:mitogen-activated protein kinase kinase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q22.31

Genomic location:

Preferred name:

NM_002755.4(MAP2K1):c.848C>T (p.Ala283Val)

Other names:

p.A283V:GCG>GTG; NM_002755.3(MAP2K1):c.848C>T

HGVS:

NC_000015.10:g.66485144C>T
NG_008305.1:g.103272C>T
NM_002755.4:c.848C>TMANE SELECT
NP_002746.1:p.Ala283Val
NP_002746.1:p.Ala283Val
LRG_725t1:c.848C>T
LRG_725:g.103272C>T
LRG_725p1:p.Ala283Val
NC_000015.9:g.66777482C>T
NM_002755.3:c.848C>T
c.848C>T

Protein change:

A283V

Links:

dbSNP: rs144080051

NCBI 1000 Genomes Browser:

rs144080051

Molecular consequence:

NM_002755.4:c.848C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000061262	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely benign (Jan 28, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001338958	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Mar 23, 2020)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000061262

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely benign
(Jan 28, 2014)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001338958

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Mar 23, 2020)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	3	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000061262.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (1)

Description

Ala283Val in exon 7 of MAP2K1: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, Egyptian jerboa and dog have a valine (Val) at this position despite high ne arby amino acid conservation. In addition, computational analyses (PolyPhen2, SI FT, AlignGVGD) do not suggest a high likelihood of impact to the protein. This v ariant has been identified in 0.1% (5/4402) of African American chromosomes by t he NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs14 4080051).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		3	not provided	1	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001338958.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Variant summary: MAP2K1 c.848C>T (p.Ala283Val) results in a non-conservative amino acid change located in the Protein kinase domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251410 control chromosomes, predominantly at a frequency of 0.0008 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is significantly above the estimated maximal expected allele frequency for a pathogenic variant in MAP2K1 causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.848C>T in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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