Submissions for variant NM_007194.4(CHEK2):c.715G>A (p.Glu239Lys)

gnomAD frequency: 0.00016  dbSNP: rs121908702

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131201	SCV000186151	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-21	criteria provided, single submitter	clinical testing	The p.E239K variant (also known as c.715G>A), located in coding exon 5 of the CHEK2 gene, results from a G to A substitution at nucleotide position 715. The glutamic acid at codon 239 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in cohorts of prostate cancer patients, unselected non-Hodgkin lymphoma patients, and BRCA-negative HBOC patients (Wu X et al. Hum. Mutat. 2006 Aug;27:742-7; Dong X et al. Am. J. Hum. Genet. 2003 Feb;72:270-80; Havranek O et al. PLoS ONE 2015 Oct;10(10):e0140819; Kraus C et al. Int. J. Cancer 2017 Jan;140(1):95-102; Girard E et al. Int J Cancer, 2019 04;144:1962-1974). In two large case-control studies, p.E239K was detected in breast cancer patients but not in healthy controls; however, these studies did not have enough carriers to demonstrate statistically increased odds (Girard E et al. Int J Cancer. 2019 04;144:1962-1974; Le Calvez-Kelm F et al. Breast Cancer Res. 2011 Jan;13:R6). In contrast, another case-control study identified p.E239K in 2/3360 healthy controls but not in 1928 breast cancer cases (Klieblova P et al. Int. J. Cancer. 2019 Oct;145(7):1782-1797). In another large study, this variant was reported in 18/60,466 breast cancer cases and in 7/53,461 controls (Dorling et al. N Engl J Med 2021 02;384:428-439) and in the combined case-control data in the ENIGMA CHEK2gether Project, this variant was reported in 15/73048 cases and 10/88658 controls, with insignificant OR of 1.63 (95% CI 0.68-4.06), p=0.24 (Stolarova L et al. Clin Cancer Res. 2023 Aug;29(16):3037-3050). Multiple functional studies have found that this alteration demonstrates partially reduced CHK2 kinase activity (Wu X et al. Hum. Mutat. 2006 Aug;27:742-7; Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44; Klieblova P et al. Int. J. Cancer 2019 Oct;145(7):1782-1797; Boonen RACM et al. Cancer Res, 2022 02;82:615-631). However, in other studies, this variant was considered functional (Delimitsou A et al. Hum. Mutat. 2019 05;40(5):631-648; Stolarova L et al. Clin Cancer Res. 2023 Aug;29(16):3037-3050). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited and conflicting at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000114762	SCV000210972	uncertain significance	not provided	2023-04-19	criteria provided, single submitter	clinical testing	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)
Invitae	RCV000205850	SCV000262054	uncertain significance	Familial cancer of breast	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 239 of the CHEK2 protein (p.Glu239Lys). This variant is present in population databases (rs121908702, gnomAD 0.03%). This missense change has been observed in individual(s) with prostate cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, colorectal cancer, non-medullary thyroid cancer, and/or breast cancer (PMID: 12533788, 21244692, 26506619, 26787654, 26976419, 27595995, 27616075, 28135145, 30303537, 31614935, 32957588, 33692755, 36468172). ClinVar contains an entry for this variant (Variation ID: 5600). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 16835864, 22419737, 30851065, 34903604). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000131201	SCV000684682	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-10	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 239 in the kinase domain of the CHEK2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown the mutant protein to exhibit partially reduced protein expression levels (PMID: 33606978), CHEK2 kinase activity (PMID: 16835864, 31050813, 31780696, 34903604) and DNA damage response (PMID: 22419737), but normal function in yeast complementation assay (PMID: 30851065). This variant has been observed in individuals affected with breast cancer (PMID: 21244692, 26976419, 27616075, 31780696, 32957588), colorectal cancer (PMID: 28135145), non-Hodgkin lymphoma (PMID: 26506619), prostate cancer (PMID: 12533788), papillary thyroid cancer (PMID: 33692755), and pheochromocytoma (PMID: 34630562). In large breast cancer case-control studies, this variant has not shown a conclusive association with increased risk of breast cancer (OR = 1.70, 95% CI 0.73 to 3.93, p=0.210 in PMID: 27595995; OR = 2.274, 95% CI 0.95 to 5.445, p=0.071 in PMID: 33471991). In addition, this variant has not shown significant association with ovarian cancer or prostate cancer in a large case-control study (PMID: 27595995). This variant has been identified in 24/282754 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000114762	SCV000698816	uncertain significance	not provided	2017-03-15	criteria provided, single submitter	clinical testing	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).
Mendelics	RCV000205850	SCV000839481	uncertain significance	Familial cancer of breast	2018-07-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000114762	SCV000885199	uncertain significance	not provided	2018-04-11	criteria provided, single submitter	clinical testing	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000114762	SCV000888122	uncertain significance	not provided	2023-02-15	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV002476934	SCV000896947	uncertain significance	Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate; Colorectal cancer	2021-11-10	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001789748	SCV002032285	uncertain significance	Predisposition to cancer	2023-04-14	criteria provided, single submitter	clinical testing	The CHEK2 c.715G>A (p.Glu239Lys) missense change has a maximum subpopulation frequency of 0.025% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive and functional assays are not in agreement about the effect of this variant on protein function (PMID: 16835864, 22419737, 30851065, 31050813, 31780696, 34903604). This variant has been reported individuals with breast cancer (21244692, 27616075, 30303537) and prostate cancer (PMID: 12533788, 16835864). It is present 2x in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Genetic Services Laboratory, University of Chicago	RCV001818140	SCV002066146	uncertain significance	not specified	2019-07-31	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131201	SCV002537633	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-11	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000114762	SCV004011387	uncertain significance	not provided	2023-04-01	criteria provided, single submitter	clinical testing	CHEK2: PS3:Supporting
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001818140	SCV004024652	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000205850	SCV004217507	uncertain significance	Familial cancer of breast	2024-03-24	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532294	SCV004711155	uncertain significance	CHEK2-related disorder	2024-01-18	criteria provided, single submitter	clinical testing	The CHEK2 c.715G>A variant is predicted to result in the amino acid substitution p.Glu239Lys. This variant has been documented in individuals with prostate cancer (Dong et al. 2003. PubMed ID: 12533788; Wu et al. 2006. PubMed ID: 16835864), breast cancer (Roeb et al. 2012. PubMed ID: 22419737) and ductal carcinoma in situ (Kraus et al. 2017, Supplemental Table 4. PubMed ID: 27616075). This variant has been reported to have a negative association with breast, prostate, and ovarian cancers among Europeans (Southey et al. 2016. PubMed ID: 27595995). Functional studies on this variant have indicated its possible role in altered acetylation (Suo et al. 2013. PubMed ID: 23298314), partially reduced kinase activity (Wu et al. 2006. PubMed ID: 16835864), and DNA damage response (Roeb et al. 2012. PubMed ID: 22419737). This variant is reported in 0.032% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as uncertain significance by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/5600/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
OMIM	RCV003333689	SCV000026130	uncertain significance	Malignant tumor of prostate	2003-02-01	no assertion criteria provided	literature only
Institute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague	RCV000114762	SCV000148657	not provided	not provided		no assertion provided	not provided
Myriad Genetics, Inc.	RCV000205850	SCV004044124	likely pathogenic	Familial cancer of breast	2023-06-26	flagged submission	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 16835864]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752].