NM_007194.4(CHEK2):c.138G>A (p.Met46Ile) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 2, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000216282.4

Allele description [Variation Report for NM_007194.4(CHEK2):c.138G>A (p.Met46Ile)]

NM_007194.4(CHEK2):c.138G>A (p.Met46Ile)

Gene:

CHEK2:checkpoint kinase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

22q12.1

Genomic location:

Preferred name:

NM_007194.4(CHEK2):c.138G>A (p.Met46Ile)

HGVS:

NC_000022.11:g.28734584C>T
NG_008150.2:g.12283G>A
NM_001005735.2:c.138G>A
NM_001257387.2:c.-640G>A
NM_001349956.2:c.138G>A
NM_007194.4:c.138G>AMANE SELECT
NM_145862.2:c.138G>A
NP_001005735.1:p.Met46Ile
NP_001336885.1:p.Met46Ile
NP_009125.1:p.Met46Ile
NP_665861.1:p.Met46Ile
LRG_302t1:c.138G>A
LRG_302:g.12283G>A
LRG_302p1:p.Met46Ile
NC_000022.10:g.29130572C>T
NG_008150.1:g.12251G>A
NM_007194.3:c.138G>A

Protein change:

M46I

Links:

dbSNP: rs876660873

NCBI 1000 Genomes Browser:

rs876660873

Molecular consequence:

NM_001257387.2:c.-640G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001005735.2:c.138G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001349956.2:c.138G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_007194.4:c.138G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_145862.2:c.138G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000278651	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Sep 2, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000278651

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Sep 2, 2022)

germline

clinical testing

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

Citation Link

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

Citations

PubMed

Comprehensive analysis and ACMG-based classification of CHEK2 variants in hereditary cancer patients.

Vargas-Parra G, Del Valle J, Rofes P, Gausachs M, Stradella A, Moreno-Cabrera JM, Velasco A, Tornero E, Menéndez M, Muñoz X, Iglesias S, López-Doriga A, Azuara D, Campos O, Cuesta R, Darder E, de Cid R, González S, Teulé A, Navarro M, Brunet J, Capellá G, et al.

Hum Mutat. 2020 Dec;41(12):2128-2142. doi: 10.1002/humu.24110. Epub 2020 Oct 14.

PubMed [citation]

PMID:: 32906215

Details of each submission

From Ambry Genetics, SCV000278651.7

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

Description

The p.M46I variant (also known as c.138G>A), located in coding exon 1 of the CHEK2 gene, results from a G to A substitution at nucleotide position 138. The methionine at codon 46 is replaced by isoleucine, an amino acid with highly similar properties. One study reports this alteration as being identified in 2/1848 individuals undergoing testing for suspected hereditary cancer (Vargas-Parra G et al. Hum Mutat, 2020 12;41:2128-2142). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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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