ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1482G>C (p.Lys494Asn) (rs767043399)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485124 SCV000568944 uncertain significance not provided 2016-10-21 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1482G>C at the cDNA level, p.Lys494Asn (K494N) at the protein level, and results in the change of a Lysine to an Asparagine (AAG>AAC) in exon 14. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Lys494Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Lysine and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. CHEK2 Lys494Asn occurs at a position that is not conserved and is located in the kinase domain (Roeb 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether CHEK2 Lys494Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000556152 SCV000633140 uncertain significance Familial cancer of breast 2020-08-14 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 494 of the CHEK2 protein (p.Lys494Asn). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CHEK2-related disease. ClinVar contains an entry for this variant (Variation ID: 420225). 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 and their clinical significance is uncertain. 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.
Ambry Genetics RCV000562793 SCV000661712 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-02 criteria provided, single submitter clinical testing The p.K494N variant (also known as c.1482G>C), located in coding exon 13 of the CHEK2 gene, results from a G to C substitution at nucleotide position 1482. The lysine at codon 494 is replaced by asparagine, an amino acid with similar properties. This amino acid position is well 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.
Color Health, Inc RCV000562793 SCV000904103 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-21 criteria provided, single submitter clinical testing This missense variant replaces lysine with asparagine at codon 494 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/233586 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.
Unit of Medical Genetics, Department of Laboratory Medicine,San Giovanni Calibita Fatebenefratelli Hospital RCV001174504 SCV001245055 likely pathogenic Li-Fraumeni syndrome 1 2020-04-28 criteria provided, single submitter clinical testing The variant c.1482G>C was reported in a case of soft tissue sarcoma with Li-Fraumeni syndrome. This variant is extremely rare and is located in an hot-spot mutation region.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000485124 SCV001470304 uncertain significance not provided 2020-05-13 criteria provided, single submitter clinical testing

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