NM_030662.4(MAP2K2):c.1187C>T (p.Thr396Met) AND RASopathy

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 5, 2019
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV001030088.6

Allele description [Variation Report for NM_030662.4(MAP2K2):c.1187C>T (p.Thr396Met)]

NM_030662.4(MAP2K2):c.1187C>T (p.Thr396Met)

Gene:

MAP2K2:mitogen-activated protein kinase kinase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.3

Genomic location:

Preferred name:

NM_030662.4(MAP2K2):c.1187C>T (p.Thr396Met)

HGVS:

NC_000019.10:g.4090614G>A
NG_007996.1:g.38515C>T
NM_030662.4:c.1187C>TMANE SELECT
NP_109587.1:p.Thr396Met
NP_109587.1:p.Thr396Met
LRG_750t1:c.1187C>T
LRG_750:g.38515C>T
LRG_750p1:p.Thr396Met
NC_000019.9:g.4090612G>A
NM_030662.3(MAP2K2):c.1187C>T
NM_030662.3:c.1187C>T

Protein change:

T396M

Links:

dbSNP: rs117945277

NCBI 1000 Genomes Browser:

rs117945277

Molecular consequence:

NM_030662.4:c.1187C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: RASopathy
Synonyms:: rasopathies; Noonan spectrum disorder
Identifiers:: MONDO: MONDO:0021060; MedGen: C5555857

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001192882	ClinGen RASopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1)	Uncertain significance (Dec 5, 2019)	germline	curation	Citation Link,
SCV001417033	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 2, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30050098, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001192882

ClinGen RASopathy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen RASopathy ACMG Specifications v1)

Uncertain significance
(Dec 5, 2019)

germline

curation

Citation Link,

SCV001417033

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 2, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Correction: Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions.

Leach NT, Wilson Mathews DR, Rosenblum LS, Zhou Z, Zhu H, Heim RA.

Genet Med. 2019 Jul;21(7):1670. doi: 10.1038/s41436-018-0128-z.

PubMed [citation]

PMID:: 30050098

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From ClinGen RASopathy Variant Curation Expert Panel, SCV001192882.1

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

Description

The c.1187C>T (p.Thr396Met) variant in MAP2K2 is present in 0.017% (11/61632) non-Finnish European alleles in gnomAD. This variant has been identified in a patient with an alternate molecular basis for disease (BP5; SCV000699629.2). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Thr396Met variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP5.

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001417033.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 396 of the MAP2K2 protein (p.Thr396Met). This variant is present in population databases (rs117945277, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of MAP2K2-related conditions (PMID: 30050098). ClinVar contains an entry for this variant (Variation ID: 279960). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MAP2K2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Sep 29, 2024

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