NM_007194.4(CHEK2):c.349A>G (p.Arg117Gly) AND Predisposition to cancer

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 13, 2021
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:: RCV001526815.6

Allele description [Variation Report for NM_007194.4(CHEK2):c.349A>G (p.Arg117Gly)]

NM_007194.4(CHEK2):c.349A>G (p.Arg117Gly)

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.349A>G (p.Arg117Gly)

Other names:

p.R117G:AGG>GGG

HGVS:

NC_000022.11:g.28725338T>C
NG_008150.2:g.21529A>G
NM_001005735.2:c.478A>G
NM_001257387.2:c.-429A>G
NM_001349956.2:c.349A>G
NM_007194.4:c.349A>GMANE SELECT
NM_145862.2:c.349A>G
NP_001005735.1:p.Arg160Gly
NP_001336885.1:p.Arg117Gly
NP_009125.1:p.Arg117Gly
NP_665861.1:p.Arg117Gly
LRG_302t1:c.349A>G
LRG_302:g.21529A>G
LRG_302p1:p.Arg117Gly
NC_000022.10:g.29121326T>C
NG_008150.1:g.21497A>G
NM_007194.3:c.349A>G
O96017:p.Arg117Gly
p.(Arg117Gly)
p.R117G

Protein change:

R117G

Links:

UniProtKB: O96017#VAR_022461; dbSNP: rs28909982

NCBI 1000 Genomes Browser:

rs28909982

Molecular consequence:

NM_001257387.2:c.-429A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001005735.2:c.478A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001349956.2:c.349A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_007194.4:c.349A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_145862.2:c.349A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Predisposition to cancer
Identifiers:

Recent activity

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translation elongation factor 1-alpha, partial [Penidiellopsis ramosus]
translation elongation factor 1-alpha, partial [Penidiellopsis ramosus]
gi|1026282561|gb|ANC90209.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001737462	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	criteria provided, single submitter (St. Jude Assertion Criteria 2020)	Likely pathogenic (May 13, 2021)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001737462

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

criteria provided, single submitter

(St. Jude Assertion Criteria 2020)

Likely pathogenic
(May 13, 2021)

germline

clinical testing

Citation Link

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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

Details of each submission

From St. Jude Molecular Pathology, St. Jude Children's Research Hospital, SCV001737462.2

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

Description

The CHEK2 c.349A>G (p.Arg117Gly) missense change has a maximum frequency of 0.019% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/22-29121326-T-C?dataset=gnomad_r2_1). Seven of seven in silico tools predict a deleterious effect of this variant on protein function (PP3). Several functional studies suggest that this variant is pathogenic, demonstrating a strongly reduced CHEK2-mediated DNA damage response, impaired kinase activity, and incomplete phosphorylation (PS3; PMID: 18725978, 22419737, 30851065, 16835864, 16982735). This variant has been identified in many cancer cases including familial breast/ovarian, prostate, pancreatic, colorectal, as well as other cancer types (PMID: 12454775, 15095295, 21244692, 26681312, 28125075, 29439820, 29659569, 29439820, 29945567, 30322717, 30256826, 28709830, 30426508, 31090900, 31263054, 31206626, 32906215, 30676620, 32906215). A case-control study showed evidence of association with breast cancer (PS4; OR = 2.26; PMID: 27595995), but no association with prostate and ovarian cancer. In addition, the variant segregated with breast cancer in three families, although it was not identified in all affected family members (PMID: 12610780) This variant is present 2x in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (BS2_supporting; https://whi.color.com/). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria: PS3, PS4, PP3, BS2_supporting.

#	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: Nov 3, 2024

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