ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1510G>C (p.Glu504Gln) (rs587782489)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131614 SCV000186630 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-10 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 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 2020-08-17 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 504 of the CHEK2 protein (p.Glu504Gln). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is present in population databases (rs587782489, ExAC 0.04%). This variant has been reported in an individual with suspected Lynch syndrome (PMID: 28577310). ClinVar contains an entry for this variant (Variation ID: 142479). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. 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 2020-12-04 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with colorectal cancer (Vargas-Parra 2017); Published functional studies demonstrate no damaging effect: cell growth and proliferation after DNA damage similar to wild type (Delimitsou 2019); This variant is associated with the following publications: (PMID: 25318351, 24356096, 28577310, 30851065)
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 2019-07-15 criteria provided, single submitter clinical testing
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 Health, Inc 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 2021-02-25 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 several individuals, including a patient with colorectal cancer (Vargas-Parra_2017), an individual tested for unspecified hereditary cancer (Yorczyk_2015) and at least an individual with breast cancer who tested negative for carrying a BRCA mutation (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. These results showed no damaging effect of this variant in a yeast-based in-vitro assay (Delimitsou_2019). Seven other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=6) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

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