Submissions for variant NM_007194.4(CHEK2):c.1180G>A (p.Glu394Lys)

gnomAD frequency: 0.00001  dbSNP: rs587780169

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212453	SCV000149895	uncertain significance	not provided	2021-05-24	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate damaging effects: Reduced kinase activity and DNA damage response (Delimitsou 2019, Kleiblova 2019); Observed in an individual with breast cancer (Kleiblova 2019); This variant is associated with the following publications: (PMID: 18571837, 24573554, 22578220, 23856246, 21765476, 30851065, 31050813, 30303537, 31398194)
Ambry Genetics	RCV000115986	SCV000184403	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-07	criteria provided, single submitter	clinical testing	The p.E394K variant (also known as c.1180G>A), located in coding exon 10 of the CHEK2 gene, results from a G to A substitution at nucleotide position 1180. The glutamic acid at codon 394 is replaced by lysine, an amino acid with similar properties. This alteration behaved as non-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). Additionally, this alteration was identified in 1/1928 breast and/or ovarian cancer patients and 0/3360 population-matched controls. In a functional assay included in this study, this variant was reported as non-functional in both in vitro kinase and human-cell based assays of KAP1 phosphorylation (Kleiblova P et al. Int. J. Cancer, 2019 Oct;145:1782-1797). This alteration was reported as functionally impaired in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Stolarova L et al. Clin Cancer Res, 2023 Aug;29:3037-3050). Finally, this variant demonstrated enrichment behavior in the presence of doxorubicin and olaparib and reduced expression of CHK2 in a drug sensitivity assay performed in MCF10A -BE3 cells with CRISPR-introduced variants (Cuella-Martin R et al. Cell, 2021 Feb;184:1081-1097.e19). 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 at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228584	SCV000289650	uncertain significance	Familial cancer of breast	2025-01-26	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 394 of the CHEK2 protein (p.Glu394Lys). This variant is present in population databases (rs587780169, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer, prostate cancer (PMID: 30303537, 31050813, 31784482, 35220195, 37842866). This variant is also known as c.1309G>A (p.Glu437Lys). ClinVar contains an entry for this variant (Variation ID: 128048). 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 disruptive. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 30851065, 31409080). 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	RCV000115986	SCV000684565	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-28	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 394 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown this variant to be damaging to protein function in in vitro and cell based kinase assays (PMID: 31050813, 33606978) and in a DNA damage repair assay in yeast (PMID: 30851065). This variant has been reported in one individual each affected with breast cancer (PMID: 31050813), prostate cancer (PMID: 37842866) and breast, ovarian or pancreatic cancer (PMID: 34026625). This variant also has been detected in a breast cancer case-control meta-analysis in 2/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000345). This variant has been identified in 5/251066 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.
Sema4, Sema4	RCV000115986	SCV002537028	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-14	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226200	SCV003923011	uncertain significance	not specified	2023-03-21	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.1180G>A (p.Glu394Lys) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251066 control chromosomes. c.1180G>A has been reported in the literature as a VUS in settings of multigene panel testing and in case control studies of individuals affected with breast cancer (example, Doddato_2021, Girard_2019, Bora_2022, Kleibova_2019). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in in-vivo characterization as damaging in a yeast functional assay evaluating ability to repair methylmethanesulfonate (MMS) induced DNA damage (example, Delimitsou_2019). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000228584	SCV003927254	uncertain significance	Familial cancer of breast	2023-05-31	criteria provided, single submitter	clinical testing	a variant of uncertain significance in the CHEK2 gene. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 394 of the CHEK2 protein (p.Glu394Lys). This variant is present in population databases (rs587780169, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 30303537, 31050813, 31784482). ClinVar contains an entry for this variant (Variation ID: 128048).this alteration is predicted to be pathogenic computational verdict based on 20 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL , SIFT , CADD, MutPred , LRT , SIFT4G , REVEL , MetaRNN and Polyphen2 vs non benign prediction. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 30851065, 31409080). 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. pathogenic/likely pathogenic variants in the CHEK2 gene cause autosomal dominant susceptibility to breast cancer (OMIM 114480).
Baylor Genetics	RCV000228584	SCV004217506	uncertain significance	Familial cancer of breast	2023-10-16	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115986	SCV004228004	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-01	criteria provided, single submitter	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV003483480	SCV004228278	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-19	criteria provided, single submitter	curation	. According to the ACMG standard criteria we chose these criteria: PS3 (strong pathogenic): Deleterious in : Stolarova et al 2023 (PMID: 37449874), Kleiblova et al 2019 (PMID: 31050813), Delimitsou et al 2019 (PMID: 30851065), PM2 (supporting pathogenic): popmax: AFR popmax AF:2.41220e-05, PP3 (supporting pathogenic): REVEL: 0.864, BayesDEL:0.394329
Fulgent Genetics, Fulgent Genetics	RCV005025182	SCV005663103	uncertain significance	Li-Fraumeni syndrome 2; Bone osteosarcoma; Familial prostate cancer	2024-02-17	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356701	SCV001551942	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CHEK2 p.Glu394Lys variant was not identified in the literature nor was it identified in the MutDB, or Zhejiang Colon Cancer Database. The variant was also identified in the following databases: dbSNP (ID: rs587780169) “With Uncertain significance allele”, ClinVar (classified uncertain significance by GeneDx, Ambry Genetics and Invitae), Clinvitae (3x), Cosmic (2x in a malignant melanoma and lymphoid neoplasm), and in control databases in 5 of 245908 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). Observations by population include European Non-Finnish in 3 of 111386 chromosomes (freq: 0.00003), and Ashkenazi Jewish in 2 of 9846 chromosomes (freq: 0.0002); it was not observed in the African, “Other”, Latino, East Asian, European Finnish, and South Asian populations. The p.Glu394 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Lys variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.