NM_030662.4(MAP2K2):c.806C>T (p.Pro269Leu) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Apr 30, 2021
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:: RCV000588108.6

Allele description [Variation Report for NM_030662.4(MAP2K2):c.806C>T (p.Pro269Leu)]

NM_030662.4(MAP2K2):c.806C>T (p.Pro269Leu)

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.806C>T (p.Pro269Leu)

Other names:

p.P269L:CCG>CTG; p.Pro269Leu

HGVS:

NC_000019.10:g.4099314G>A
NG_007996.1:g.29815C>T
NM_030662.4:c.806C>TMANE SELECT
NP_109587.1:p.Pro269Leu
NP_109587.1:p.Pro269Leu
LRG_750t1:c.806C>T
LRG_750:g.29815C>T
LRG_750p1:p.Pro269Leu
NC_000019.9:g.4099312G>A
NM_030662.3:c.806C>T

Protein change:

P269L

Links:

dbSNP: rs368064728

NCBI 1000 Genomes Browser:

rs368064728

Molecular consequence:

NM_030662.4:c.806C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000207961	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Mar 4, 2015)	germline	clinical testing	Citation Link,
SCV000699643	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Jul 10, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV002541477	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 30, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000207961

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Mar 4, 2015)

germline

clinical testing

Citation Link,

SCV000699643

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Jul 10, 2017)

germline

clinical testing

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

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV002541477

Mayo Clinic Laboratories, Mayo Clinic

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 30, 2021)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	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

Germline Mutations in Predisposition Genes in Pediatric Cancer.

Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, Hedges D, Ma X, Zhou X, Yergeau DA, Wilkinson MR, Vadodaria B, Chen X, McGee RB, Hines-Dowell S, Nuccio R, Quinn E, Shurtleff SA, Rusch M, Patel A, Becksfort JB, Wang S, et al.

N Engl J Med. 2015 Dec 10;373(24):2336-2346. doi: 10.1056/NEJMoa1508054. Epub 2015 Nov 18.

PubMed [citation]

PMID:: 26580448
PMCID:: PMC4734119

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From GeneDx, SCV000207961.12

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

Description

p.Pro269Leu (CCG>CTG): c.806 C>T in exon 7 of the MAP2K2 gene (NM_030662.3).A variant of unknown significance has been identified in the MAP2K2 gene. The P269L variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The P269L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P269L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is well conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. One missense mutation in a nearby residue (K273R) has been reported in association with Cardio-Facio-Cutaneous (CFC) syndrome, supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.This variant has been observed to be maternally inherited. The variant is found in NOONAN panel(s).

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000699643.1

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

Description

Variant summary: The MAP2K2 c.806C>T (p.Pro269Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). The variant of interest has been found in a large, broad control population, ExAC in 3/80512 control chromosomes at a frequency of 0.0000373, which is approximately 15 times the estimated maximal expected allele frequency of a pathogenic MAP2K2 variant (0.0000025), suggesting this variant is likely a benign polymorphism. This variant was reported in one case of infant ALL without strong evidence for causality (Zhang_BRCA_NEJM_2015). One clinical diagnostic laboratory classified this variant as uncertain significance (cited as a maternally inherited variant identified in pt in NSRD panel; no clinical info on pt and the mother provided by submitter). Taken together, this variant is classified as VUS-possibly 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

From Mayo Clinic Laboratories, Mayo Clinic, SCV002541477.1

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

#	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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