NM_007194.4(CHEK2):c.715G>A (p.Glu239Lys) AND not provided
- Germline classification:
- Uncertain significance (6 submissions)
- Last evaluated:
- Apr 19, 2023
- Review status:
- 2 stars out of maximum of 4 starscriteria provided, multiple submitters, no conflicts
- Somatic classification
of clinical impact: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Somatic classification
of oncogenicity: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Record status:
- current
- Accession:
- RCV000114762.26
Allele description [Variation Report for NM_007194.4(CHEK2):c.715G>A (p.Glu239Lys)]
NM_007194.4(CHEK2):c.715G>A (p.Glu239Lys)
- 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.715G>A (p.Glu239Lys)
- Other names:
- chr22:29,107,974C>T; p.E239K:GAG>AAG
- HGVS:
- NC_000022.11:g.28711986C>T
- NG_008150.2:g.34881G>A
- NM_001005735.2:c.844G>A
- NM_001257387.2:c.52G>A
- NM_001349956.2:c.514G>A
- NM_007194.4:c.715G>AMANE SELECT
- NM_145862.2:c.715G>A
- NP_001005735.1:p.Glu282Lys
- NP_001244316.1:p.Glu18Lys
- NP_001336885.1:p.Glu172Lys
- NP_009125.1:p.Glu239Lys
- NP_665861.1:p.Glu239Lys
- LRG_302t1:c.715G>A
- LRG_302:g.34881G>A
- LRG_302p1:p.Glu239Lys
- NC_000022.10:g.29107974C>T
- NG_008150.1:g.34849G>A
- NM_001005735.1:c.844G>A
- NM_007194.3:c.715G>A
- O96017:p.Glu239Lys
- p.E239K
This HGVS expression did not pass validation- Protein change:
- E172K; GLU239LYS
- Links:
- UniProtKB: O96017#VAR_019106; OMIM: 604373.0011; dbSNP: rs121908702
- NCBI 1000 Genomes Browser:
- rs121908702
- Molecular consequence:
- NM_001005735.2:c.844G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001257387.2:c.52G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001349956.2:c.514G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_007194.4:c.715G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_145862.2:c.715G>A - missense variant - [Sequence Ontology: SO:0001583]
- Observations:
- 1
Condition(s)
- Synonyms:
- none provided
- Identifiers:
- MedGen: C3661900
Assertion and evidence details
| Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
|---|---|---|---|---|---|---|
| SCV000148657 | Institute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague | no classification provided | not provided | germline, somatic | not provided | |
| SCV000210972 | GeneDx | criteria provided, single submitter (GeneDx Variant Classification Process June 2021) | Uncertain significance (Apr 19, 2023) | germline | clinical testing | |
| SCV000698816 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) | Uncertain significance (Mar 15, 2017) | germline | clinical testing | PubMed (7) LabCorp Variant Classification Summary - May 2015.docx, |
| SCV000885199 | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) | Uncertain significance (Apr 11, 2018) | germline | clinical testing | |
| SCV000888122 | Quest Diagnostics Nichols Institute San Juan Capistrano | criteria provided, single submitter (Quest Diagnostics criteria) | Uncertain significance (Feb 15, 2023) | unknown | clinical testing | |
| SCV004011387 | CeGaT Center for Human Genetics Tuebingen | criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) | Uncertain significance (Apr 1, 2023) | germline | clinical testing |
Summary from all submissions
| Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
|---|---|---|---|---|---|---|---|---|
| not provided | germline | not provided | not provided | not provided | not provided | not provided | not provided | literature only |
| not provided | germline | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing |
| not provided | germline | yes | 1 | not provided | not provided | not provided | not provided | clinical testing |
| not provided | somatic | not provided | not provided | not provided | not provided | not provided | not provided | literature only |
| not provided | unknown | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing |
Citations
PubMed
Association of Germline CHEK2 Gene Variants with Risk and Prognosis of Non-Hodgkin Lymphoma.
Havranek O, Kleiblova P, Hojny J, Lhota F, Soucek P, Trneny M, Kleibl Z.
PLoS One. 2015;10(10):e0140819. doi: 10.1371/journal.pone.0140819.
- PMID:
- 26506619
- PMCID:
- PMC4624763
Mutations in CHEK2 associated with prostate cancer risk.
Dong X, Wang L, Taniguchi K, Wang X, Cunningham JM, McDonnell SK, Qian C, Marks AF, Slager SL, Peterson BJ, Smith DI, Cheville JC, Blute ML, Jacobsen SJ, Schaid DJ, Tindall DJ, Thibodeau SN, Liu W.
Am J Hum Genet. 2003 Feb;72(2):270-80. Epub 2003 Jan 17.
- PMID:
- 12533788
- PMCID:
- PMC379222
Details of each submission
From Institute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague, SCV000148657.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | not provided | PubMed (1) |
| 2 | not provided | not provided | not provided | not provided | not provided | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | not provided | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
| 2 | somatic | not provided | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From GeneDx, SCV000210972.17
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
Description
Published functional studies are conflicting: some demonstrate reduced or intermediate kinase activity, stability, and DNA damage response while others report activity similar to wild type (Wu et al., 2006; Roeb et al., 2012; Scarpa et al., 2017; Delimitsou et al., 2019; Dutil et al., 2019; Kleiblova et al., 2019; Boonen et al., 2022); Observed in individuals with a history of breast cancer, prostate cancer, colorectal cancer, non-Hodgkin lymphoma, or other cancers (Dong et al., 2003; Le Calvez-Kelm et al., 2011; Havranek et al., 2015; Kraus et al., 2016; Tung et al., 2016; Yurgelun et al., 2017; Dutil et al., 2019; Girard et al., 2019; Greville-Heygate et al., 2020; Dorling et al., 2021; Srivastava et al., 2021; Guindalini et al., 2022; McDonald et al., 2022; Wagener et al., 2022); Case control studies suggest this variant is not associated with breast, ovarian, or prostate cancer (Southey et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as c.844G>A, p.E282K; This variant is associated with the following publications: (PMID: 12533788, 21244692, 25318351, 16835864, 22419737, 23298314, 25525159, 16941491, 26506619, 26976419, 26787654, 28135136, 28135137, 27616075, 28199314, 28135145, 31050813, 30851065, 31780696, 32957588, 34426522, 27595995, 33309985, 33692755, 19782031, 32923877, 35264596, 33471991, 36315513, 30303537, 36468172, 34903604)
| # | 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, SCV000698816.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (7) |
Description
Variant summary: The CHEK2 c.715G>A (p.Glu239Lys) variant located in the kinase domain (via InterPro) involves the alteration of a conserved nucleotide and is predicted to be benign by 3/4 in silico tools (SNPs&GO not captured due to low reliability index). This variant was found in 19/209626 control chromosomes including broad and large populations from ExAC at a frequency of 0.0000906, which does not exceed the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0003125). This variant has been reported as a germline variant in patients with breast cancer, ovarian cancer, prostate cancer and non-Hodgkin lymphoma (Dong 2003, Le Calvez-Kelm 2011, Tung_2015, Havranek 2015, Roeb_2015, Kraus_2016, Southey_2016). However, there are no cosegregation studies to confirm its pathogenicity or lack of pathogenicity. It has also been reported to co-occur with other rare missense variants, namely CHEK2 R346H, BRIP1 p.Arg416Trp, BRIP1 p.Ile640Thr (Calvez-Kelm_2011, Tung_2015) and BRCA1 p.Ser1715Cys (one internal sample). In a multicentre large case-control study, this variant was not found to confer a statistically significant increase risk for breast, ovarian and prostate cancers (Southey_2016). In the study, odds ratio for breast, ovarian and prostate cancers were 1.47 (95% CI: 0.6-3.64; p-value: 0.5), 1.47 (95% CI: 0.42-5.22; p-value: 0.54) and 1.47 (95% CI: 0.41-5.35; p-value: 0.55), respectively. Pathogenic variants in CHEK2 gene constitute risk alleles that confer low risk for breast cancer (e.g. CHEK2 1100delC leads to 2-3 fold increase in breast cancer risk in women and a 10 fold increase of risk in men; GeneReviews). Therefore, this variant could be an intermediate risk allele. This is also supported by functional studies that suggest this variant to have an intermediate effect in yeast-based in vivo DNA damage response and was found to partially reduce the kinase activity (Wu_2006, Roeb_2012). Multiple clinical diagnostic laboratories in ClinVar have classified this variant as uncertain significance. Taken together, this variant is currently classified as Variant of Unknown Significance (VUS).
| # | 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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000885199.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
Description
The CHEK2: p.Glu239Lys variant (rs121908702) has been reported in association with colorectal, prostate, breast, and ovarian cancers, including control groups (Yurgelun 2017, Kraus 2017, Dong 2003, and Southey 2016). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.03 percent in the European Finnish population (identified on 8 out of 25,726 chromosomes) and has been reported to the ClinVar database (Variation ID: 5600). Reconstitution of this variant in yeast cells lacking CHEK2 showed a “moderate†decrease of growth compared to WT after DNA damage induction by methyl methanesulfonate (Roeb 2012). This variant is moderately conserved in the kinase domain of the CHEK2 protein and has been shown to reduce the phosphorylation activity of the enzyme with model substrate (Wu 2006); however computational predictors indicate a neutral effect on protein structure and function (SIFT: tolerated, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Glu239Lys variant with certainty.
| # | 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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000888122.5
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (17) |
Description
In the published literature, this variant has been reported in individuals affected with breast and/or ovarian cancer (PMIDs: 35264596 (2022), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/CHEK2), 32957588 (2020), 30303537 (2019), 27616075 (2017), 27595995 (2016), 26976419 (2016), 26787654 (2016), 25186627 (2015), 21244692 (2011)), prostate cancer (PMIDs: 16941491 (2006), 12533788 (2003)), colorectal cancer (PMIDs: 33298767 (2021), 28135145 (2017)), as well as in healthy individuals (PMIDs: 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/CHEK2), 27595995 (2016)). In addition, functional studies in the published literature demonstrated that this variant has an intermediate effect on CHEK2 activity (PMIDs: 34903604 (2022), 30851065 (2019), 31050813 (2019), 31780696 (2019), 22419737 (2012), 16835864 (2006)), however further studies are needed to determine the global effect of this variant on CHEK2 protein activity. The frequency of this variant in the general population, 0.00025 (9/35436 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.
| # | 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 CeGaT Center for Human Genetics Tuebingen, SCV004011387.6
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 1 | not provided | not provided | clinical testing | not provided |
Description
CHEK2: PS3:Supporting
| # | 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 | |
Last Updated: Apr 20, 2024