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 Insufficient or conflicting evidence
Invitae RCV000198676 SCV000254928 uncertain significance Familial cancer of breast 2019-12-27 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 undergoing hereditary cancer testing (PMID: 25318351). 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 2018-04-25 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1510G>C at the cDNA level, p.Glu504Gln (E504Q) at the protein level, and results in the change of a Glutamic Acid to a Glutamine (GAA>CAA). This variant was observed in at least one individual referred for hereditary cancer testing and in an individual with colorectal cancer (Yorczyk 2014, Vargas-Parra 2017). Although this variant was observed in large population cohorts, population data in this region of CHEK2 are not considered reliable due to high pseudogene homology (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CHEK2 Glu504Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
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; Osteosarcoma; Malignant tumor of prostate 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000131614 SCV000911096 likely benign Hereditary cancer-predisposing syndrome 2016-03-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001251282 SCV001426814 uncertain significance not specified 2020-07-22 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) and an indivdual tested for unspecified hereditary cancer (Yorczyk_2015). 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 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. They have cited the variant as uncertain significance (n=6) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

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