ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.715G>C (p.Glu239Gln)

dbSNP: rs121908702
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000573178 SCV000673249 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-24 criteria provided, single submitter clinical testing The p.E239Q variant (also known as c.715G>C), located in coding exon 5 of the CHEK2 gene, results from a G to C substitution at nucleotide position 715. The glutamic acid at codon 239 is replaced by glutamine, an amino acid with highly similar properties. 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, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000573178 SCV000689716 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-22 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with glutamine at codon 239 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). This variant was reported to have normal function in a yeast-based DNA damage response assay (PMID: 30851065). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251364 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.
Invitae RCV001217899 SCV001389758 uncertain significance Familial cancer of breast 2022-08-16 criteria provided, single submitter clinical testing 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. Experimental studies have shown that this missense change does not substantially affect CHEK2 function (PMID: 30851065). 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. ClinVar contains an entry for this variant (Variation ID: 485517). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. This variant is present in population databases (rs121908702, gnomAD 0.0009%). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 239 of the CHEK2 protein (p.Glu239Gln).

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