ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.715G>A (p.Glu239Lys) (rs121908702)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131201 SCV000186151 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-31 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 a familial prostate cancer kindred in one of two affected brothers tested; it has also been reported in one individual from an unselected cohort of non-Hodgkin lymphoma patients and in a cohort of BRCA-negative hereditary breast/ovarian cancer patients. (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). One additional study reported this variant in 1/84 unselected primary prostate tumor samples as a germline or early somatic change with normal nuclear localization. This variant is in the kinase domain of the CHK2 protein and the authors found that it resulted in partially reduced CHK2 kinase activity (Wu X et al. Hum. Mutat. 2006 Aug;27:742-7). In a large case-control study, p.E239K was detected in 2/1303 breast cancer patients and 0/1109 healthy controls (Le Calvez-Kelm F et al. Breast Cancer Res. 2011 Jan;13:R6). In contrast, another case control study identifed p.E239K in 2/3360 healthy controls but not in 1928 breast cancer cases; this study, like Wu et al, also found partially reduced CHK2 kinase activity (Klieblova P et al. Int. J. Cancer 2019 Oct;145(7):1782-1797). In a CHK2-mediated DNA damage response assay, the alteration had an intermediate or partial response in one study (Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44), but behaved as functional in an in vivo, yeast-based growth rate assay in another (Delimitsou A et al. Hum. Mutat. 2019 05;40(5):631-648). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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 2018-12-13 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.715G>A at the cDNA level, p.Glu239Lys (E239K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant has been observed in individuals with a personal history of breast cancer, prostate cancer, colorectal cancer, or non-Hodgkin lymphoma, as well as in healthy controls (Dong 2003, Le Calvez-Kelm 2011, Havranek 2015, Kraus 2016, Tung 2016, Yurgelun 2017), but was not shown to be significantly associated with breast or prostate cancer (Southey 2016). Also published as CHEK2 p.Glu282Lys (E282K) based on an alternate transcript, this variant was shown to have reduced kinase activity in two different studies (Wu 2006, Scarpa 2017), while a yeast-based assay found the variant to have an intermediate response to DNA damage (Roeb 2012). CHEK2 Glu239Lys was observed at an allele frequency of 0.03% (8/25726) in individuals of Finnish ancestry in large population cohorts (Lek 2016). CHEK2 Glu239Lys is located within the protein kinase domain (Cai 2009, Roeb 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CHEK2 Glu239Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000205850 SCV000262054 uncertain significance Familial cancer of breast 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 239 of the CHEK2 protein (p.Glu239Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs121908702, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with familial prostate cancer and an individual affected with non-Hodgkin lymphoma (PMID: 12533788, 26506619). It has also been reported in an individual affected with colorectal cancer (PMID: 28135145), in a family with non-medullary thyroid cancer (PMID: 31614935), and in individuals affected with breast cancer (PMID: 21244692, 26976419, 26787654, 27616075, 30303537). In one case-control study, this variant was reported in 2/1303 cases and 0/1109 controls; however, one of those cases also carried other rare CHEK2 missense variants (PMID: 21244692). In another case-control study, there was no evidence for association of this variant with an increased risk for breast cancer, ovarian cancer, or prostate cancer (PMID: 27595995). ClinVar contains an entry for this variant (Variation ID: 5600). This variant has been reported to have conflicting or insufficient data to determine the effect on CHEK2 protein function (PMID: 22419737, 16835864, 30851065). 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 Health, Inc RCV000131201 SCV000684682 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-04 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 239 in 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 reported this variant to be partially to fully functional in yeast complementation assays, and kinase assays in mammalian cells and in vitro (PMID: 16835864, 22419737, 30851065, 31050813, 31780696). 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), and prostate cancer (PMID: 12533788). A large, multi-center case-control study has shown that this variant is not significantly associated with increased risk of breast, ovarian or prostate cancer (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 2018-09-18 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765622 SCV000896947 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000005948 SCV000026130 pathogenic Prostate cancer, somatic 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

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