NM_007194.4(CHEK2):c.349A>G (p.Arg117Gly) AND CHEK2-related cancer predisposition

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Mar 25, 2022
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:: RCV004556728.2

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]

Observations:

Condition(s)

Name:: CHEK2-related cancer predisposition
Synonyms:: CHEK2-Related Cancer Susceptibility
Identifiers:: MONDO: MONDO:0700271; MedGen: CN377760

Recent activity

Clear Turn Off Turn On

ankyrin repeat and SOCS box protein 13 isoform X1 [Cygnus olor]
ankyrin repeat and SOCS box protein 13 isoform X1 [Cygnus olor]
gi|2022791011|ref|XP_040401786.1|

Protein
ankyrin repeat and SOCS box protein 13 isoform X1 [Cygnus atratus]
ankyrin repeat and SOCS box protein 13 isoform X1 [Cygnus atratus]
gi|1876069161|ref|XP_035422490.1|

Protein

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001749392	GenomeConnect - Invitae Patient Insights Network	no classification provided	not provided	unknown	phenotyping only
SCV002318957	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 25, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 18725978, 16982735, 22419737, 12454775, 12610780, 21244692, 28503720, 25741868
SCV004801674	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Likely pathogenic (May 15, 2018)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001749392

GenomeConnect - Invitae Patient Insights Network

no classification provided

not provided

unknown

phenotyping only

SCV002318957

DASA

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 25, 2022)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV004801674

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSLVariantClassificationCriteria RUGD 01 April 2020)

Likely pathogenic
(May 15, 2018)

unknown

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, phenotyping only
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

CHEK2 mutations affecting kinase activity together with mutations in TP53 indicate a functional pathway associated with resistance to epirubicin in primary breast cancer.

Chrisanthar R, Knappskog S, Løkkevik E, Anker G, Østenstad B, Lundgren S, Berge EO, Risberg T, Mjaaland I, Maehle L, Engebretsen LF, Lillehaug JR, Lønning PE.

PLoS One. 2008 Aug 26;3(8):e3062. doi: 10.1371/journal.pone.0003062.

PubMed [citation]

PMID:: 18725978
PMCID:: PMC2518116

Rare germ line CHEK2 variants identified in breast cancer families encode proteins that show impaired activation.

Sodha N, Mantoni TS, Tavtigian SV, Eeles R, Garrett MD.

Cancer Res. 2006 Sep 15;66(18):8966-70.

PubMed [citation]

PMID:: 16982735

See all PubMed Citations (8)

Details of each submission

From GenomeConnect - Invitae Patient Insights Network, SCV001749392.1

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

Description

Variant interpreted as Likely pathogenic and reported on 03-13-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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

From DASA, SCV002318957.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (8)

Description

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 18725978; 16982735; 22419737) - PS3_moderate. The c.349A>G;p.(Arg117Gly) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 128071; PMID: 12454775; PMID: 12610780; PMID: 21244692; PMID: 28503720) -PS4. The variant is present at low allele frequencies population databases (rs28909982 – gnomAD 0.001132%; ABraOM 0.001281 frequency - http://abraom.ib.usp.br.) - PM2_supporting. In summary, the currently available evidence indicates that the variant is likely pathogenic

#	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		1	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV004801674.1

#	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), also referred to c.478A>G (Arg160Gly), missense variant has been identified in individuals with a phenotype consistent with CHEK2-related cancer susceptibility. In two individuals, other pathogenic BRCA2 and CHEK2 variants were also identified (Sodha et al. 2002; Schutte et al. 2003; Le Calvez-Kelm et al. 2011; Southey et al. 2016; Susswein et al. 2016). In a large case-control study, Southey et al. (2016) showed that the p.(Arg117Gly) variant was significantly associated with breast cancer in European women (odds ratio of 2.26). In this study, odd ratios were not statistically significant for prostate cancer or ovarian cancer. The variant segregated with breast cancer in one family whereas in two families incomplete segregation was observed whereby two affected individuals did not carry the variant (Schutte et al. 2003). The highest frequency of this allele in the Genome Aggregation Database is 0.000186 in the European (non-Finnish) population (version 2.1.1). Functional studies in cells lines demonstrated reduced protein expression and stability, and impaired phosphorylation and kinase activity of the variant protein when compared to wildtype protein. However, the variant protein dimerized efficiently to wildtype CHEK2 (Sodha et al. 2006; Wu et al. 2006; Chrisanthar et al. 2008). Multiple lines of computational evidence suggest the variant may impact the gene or gene product. Based on the available evidence, the c.349A>G p.(Arg117Gly) variant is classified as likely pathogenic for CHEK2-related breast cancer susceptibility.

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

Last Updated: Nov 3, 2024

ClinVar

Relating variation to medicine