Submissions for variant NM_007194.4(CHEK2):c.1510G>C (p.Glu504Gln)

dbSNP: rs587782489

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131614	SCV000186630	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-30	criteria provided, single submitter	clinical testing	The p.E504Q variant (also known as c.1510G>C), located in coding exon 13 of the CHEK2 gene, results from a G to C substitution at nucleotide position 1510. The glutamic acid at codon 504 is replaced by glutamine, an amino acid with highly similar properties. This alteration was detected in 0/1054 Hispanic BRCA1/2-negative probands with hereditary breast cancer and 2/1189 controls (Weitzel JN et al. Cancer, 2019 Aug;125:2829-2836). 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 poorly 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.
Invitae	RCV000198676	SCV000254928	uncertain significance	Familial cancer of breast	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 504 of the CHEK2 protein (p.Glu504Gln). This variant is present in population databases (rs587782489, gnomAD 0.03%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 28577310). ClinVar contains an entry for this variant (Variation ID: 142479). 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: 28577310). 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	RCV000214263	SCV000279274	uncertain significance	not provided	2023-09-11	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; 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: 25318351, 24356096, 30851065, 33471991, 31206626, 28577310)
Counsyl	RCV000198676	SCV000784856	uncertain significance	Familial cancer of breast	2017-01-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000214263	SCV000888110	uncertain significance	not provided	2023-04-20	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00026 (9/35206 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, this variant has been reported in an individual undergoing hereditary cancer testing and an individual with a Lynch-like Syndrome phenotype (PMID: 25318351 (2014), 28577310 (2017)). It has also been detected in a healthy, cancer-free Hispanic individual (PMID: 31206626 (2019)). In addition, this variant has been reported as having a benign effect on CHEK2 protein activity using a yeast based functional assay (PMID: 30851065 (2019)). 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.
Fulgent Genetics, Fulgent Genetics	RCV000764369	SCV000895404	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
Color Diagnostics, LLC DBA Color Health	RCV000131614	SCV000911096	likely benign	Hereditary cancer-predisposing syndrome	2016-03-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251282	SCV001426814	uncertain significance	not specified	2023-02-13	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.1510G>C (p.Glu504Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 233634 control chromosomes, predominantly at a frequency of 0.00026 within the Latino subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1510G>C has been reported in the literature in an individual with MSH2-deficient colorectal cancer in whom a germline MSH2 alteration was not reportedly identified (example, Vargas-Parra_2017), as a VUS in settings of multigene panel testing in an individual tested for an unspecified hereditary cancer (example, Yorczyk_2015) and as a VUS in settings of multigene panel testing in an individual with BRCA-negative breast cancer (example, Weitzel_2019). These reports 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 (Delimitsou_2019). These results showed no damaging effect of this variant in a yeast-based in-vitro assay. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=7; likely benign, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Sema4, Sema4	RCV000131614	SCV002537386	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-12	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000198676	SCV004020103	likely benign	Familial cancer of breast	2023-03-08	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].