Submissions for variant NM_007194.4(CHEK2):c.904G>A (p.Glu302Lys)

gnomAD frequency: 0.00001  dbSNP: rs587782460

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131547	SCV000186547	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-26	criteria provided, single submitter	clinical testing	The p.E302K variant (also known as c.904G>A), located in coding exon 7 of the CHEK2 gene, results from a G to A substitution at nucleotide position 904. The glutamic acid at codon 302 is replaced by lysine, an amino acid with similar properties. This alteration behaved as semi-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). In addition, in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells, this alteration demonstrated impaired function as assessed by KAP1 phosphorylation, but retained intermediate levels of functionality as assessed by CHK2 autophosphorylation (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 at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000199375	SCV000254954	uncertain significance	Familial cancer of breast	2024-01-08	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 302 of the CHEK2 protein (p.Glu302Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 142430). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 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.
GeneDx	RCV000759047	SCV000278925	uncertain significance	not provided	2022-05-20	criteria provided, single submitter	clinical testing	Observed in at least one individual undergoing multigene hereditary cancer panel testing (Mu 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate intermediate results on a yeast-based assay (Delimitsou 2019); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.1033G>A; p.(E345K); This variant is associated with the following publications: (PMID: 22419737, 19782031, 27720647, 30851065)
Color Diagnostics, LLC DBA Color Health	RCV000131547	SCV000684693	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-12	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 302 of the CHEK2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant has been shown to have intermediate impact on function in a yeast-based complementation assay, and intermediate impact on autophosphorylation and KAP1 phosphorylation in a mammalian cell complementation assay (PMID: 30851065, 37449874). This variant has been reported in individuals affected with breast cancer (PMID: 32658311, 32885271). In a large breast cancer case-control meta analysis conducted by the ENIGMA consortium, this variant was reported in 5/73048 cases and 2/88658 unaffected controls (PMID: 37449874). This variant has not been identified 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.
Counsyl	RCV000199375	SCV000785010	uncertain significance	Familial cancer of breast	2017-03-16	criteria provided, single submitter	clinical testing
Mendelics	RCV000199375	SCV000839476	uncertain significance	Familial cancer of breast	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759047	SCV000888126	uncertain significance	not provided	2017-10-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192412	SCV001360507	uncertain significance	not specified	2023-10-30	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.904G>A (p.Glu302Lys) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 204154 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.904G>A has been reported in the literature as a VUS in settings of multigene panel testing among individuals affected with Breast Cancer and/or undergoing testing for Hereditary Cancer (example, Mu_2016, Delimitsou_2019, Guindalini_2022, de Oliveira_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function in a yeast-based functional analysis (Delemitsou_2019). The most pronounced variant effect results in intermediate levels activity. The following publications have been ascertained in the context of this evaluation (PMID: 35643632, 30851065, 35264596, 27720647, 35534704). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=9, LP, n=1 not providing specific evidence). Based on the evidence outlined above, the variant was classified as uncertain significance.
Division of Medical Genetics, University of Washington	RCV000199375	SCV001434261	uncertain significance	Familial cancer of breast	2020-05-05	criteria provided, single submitter	clinical testing	To our knowledge, this sequence variant has not been previously reported in the literature. This variant is not present in gnomAD database (https://gnomad.broadinstitute.org/). In silico tools evaluating evolutionary conservation and impact on protein structure and function suggest that this variant may have a deleterious effect; however, there are no functional studies to verify or refute these predictions. At this time, it is unknown at this time whether or not this variant increases cancer risk; therefore, we interpret it as a variant of uncertain significance. PM2; PP3
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002292378	SCV002584938	uncertain significance	Predisposition to cancer	2022-06-29	criteria provided, single submitter	clinical testing	The CHEK2 c.904G>A (p.Glu302Lys) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, however a yeast-based functional study demonstrates an intermediate impact on CHEK2 protein function (PMID: 30851065). In summary, the evidence currently available is insufficient to determine the role of this variant in cancer predisposition. It has therefore been classified as of uncertain significance.
Baylor Genetics	RCV000199375	SCV004217594	uncertain significance	Familial cancer of breast	2023-08-21	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000759047	SCV001549415	uncertain significance	not provided		no assertion criteria provided	clinical testing	The CHEK2 p.Glu302Lys variant was identified in 1 of 40,000 chromosomes (frequency: 0.00003) from patient undergoing multigene hereditary cancer panel testing (Mu 2016). The variant was also identified in dbSNP (ID: rs587782460) as “With Uncertain significance allele” and ClinVar (as uncertain significance by Ambry Genetics, Invitae, GeneDx, and four other submitters). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). A yeast-based assay determined this variant produced a protein that was had intermediate function (Delimitsou 2019). The p.Glu302 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.
Myriad Genetics, Inc.	RCV000199375	SCV004020233	likely pathogenic	Familial cancer of breast	2023-03-09	flagged submission	clinical testing	This variant is considered likely pathogenic. 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].