Submissions for variant NM_007194.4(CHEK2):c.1582G>A (p.Glu528Lys)

gnomAD frequency: 0.00006  dbSNP: rs138040612

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131443	SCV000186427	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-21	criteria provided, single submitter	clinical testing	The p.E528K variant (also known as c.1582G>A), located in coding exon 14 of the CHEK2 gene, results from a G to A substitution at nucleotide position 1582. The glutamic acid at codon 528 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in the germline of one Chinese individual diagnosed with diffuse large B-cell lymphoma (de Miranda NF et al. J. Exp. Med. 2013 Aug;210:1729-42). In addition, this alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat., 2019 05;40:631-648). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000588204	SCV000210999	uncertain significance	not provided	2023-08-23	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colon cancer and lymphoma (de Miranda et al., 2013; Yurgelun et al., 2017); Published functional studies demonstrate no damaging effect: cell growth and proliferation after DNA damage similar to wild type (Delimitsou et al., 2019); This variant is associated with the following publications: (PMID: 23960188, 28135145, 28211887, 31398194, 32906215, 30851065)
Invitae	RCV000233973	SCV000289672	uncertain significance	Familial cancer of breast	2024-01-03	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 528 of the CHEK2 protein (p.Glu528Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with diffuse large B cell lymphoma and colorectal cancer (PMID: 23960188, 28135145, 34326862). ClinVar contains an entry for this variant (Variation ID: 142361). 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 have shown that this missense change does not substantially affect 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.
Counsyl	RCV000233973	SCV000489379	uncertain significance	Familial cancer of breast	2016-09-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131443	SCV000684611	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-03	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 528 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. An experimental functional study has been shown this variant to be neutral in a yeast based DNA damage repair assay (PMID: 30851065). This variant has been reported in individuals affected with colorectal cancer in the literature (PMID: 28135145). This variant has been identified in 8/265030 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	RCV001290447	SCV000698787	uncertain significance	not specified	2021-01-05	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.1582G>A (p.Glu528Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.1e-05 in 233632 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1582G>A has been reported in the literature as a germline variant in individuals with diffuse large B-cell lymphoma (DLBCL) and colorectal cancer (e.g. deMiranda_2013, Yurgelun_2017). These reports do not provide unequivocal conclusions about association of the variant with disease. At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant showed no damaging effects in a yeast-based assay (e.g. Delimitsou_2019). Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Illumina Laboratory Services, Illumina	RCV001147094	SCV001307872	uncertain significance	CHEK2-Related Cancer Susceptibility	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588204	SCV001470306	uncertain significance	not provided	2023-01-31	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in an individual with colorectal cancer (PMID: 28135145 (2017)). A yeast functional assay found that this variant had a benign effect on protein function (PMID: 30851065 (2019)). The frequency of this variant in the general population, 0.00004 (5/124096 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4	RCV000131443	SCV002537399	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-17	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002492512	SCV002792421	uncertain significance	Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate; Colorectal cancer	2022-02-14	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000233973	SCV004020216	uncertain significance	Familial cancer of breast	2023-03-09	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000233973	SCV004217595	uncertain significance	Familial cancer of breast	2023-08-21	criteria provided, single submitter	clinical testing