ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1448A>G (p.His483Arg)

gnomAD frequency: 0.00001  dbSNP: rs587780177
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000679674 SCV000149911 uncertain significance not provided 2019-07-23 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30851065)
Ambry Genetics RCV000116002 SCV000185145 uncertain significance Hereditary cancer-predisposing syndrome 2023-09-16 criteria provided, single submitter clinical testing The p.H483R variant (also known as c.1448A>G), located in coding exon 12 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1448. The histidine at codon 483 is replaced by arginine, an amino acid with highly similar properties. This alteration behaved as non-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat., 2019 05;40:631-648). This alteration was also reported as functionally impaired in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Stolarova L et al. Clin Cancer Res, 2023 Aug;29:3037-3050). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000199678 SCV000254926 uncertain significance Familial cancer of breast 2023-12-17 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 483 of the CHEK2 protein (p.His483Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 128061). 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 disruptive. 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.
Color Diagnostics, LLC DBA Color Health RCV000116002 SCV000684595 uncertain significance Hereditary cancer-predisposing syndrome 2022-09-19 criteria provided, single submitter clinical testing This missense variant replaces histidine with arginine at codon 483 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown this variant to disrupt CHEK2 function in a DNA damage repair assay in yeast (PMID: 30851065). This variant has been reported a child affected with acute lymphocytic leukemia (PMID: 26580448). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
PreventionGenetics, part of Exact Sciences RCV000679674 SCV000806870 uncertain significance not provided 2017-08-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679674 SCV001470303 uncertain significance not provided 2020-01-21 criteria provided, single submitter clinical testing
Baylor Genetics RCV000199678 SCV004217566 uncertain significance Familial cancer of breast 2023-09-07 criteria provided, single submitter clinical testing

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