ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1415A>G (p.Lys472Arg) (rs1064793511)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478318 SCV000566297 uncertain significance not provided 2016-07-13 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1415A>G at the cDNA level, p.Lys472Arg (K472R) at the protein level, and results in the change of a Lysine to an Arginine (AAG>AGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Lys472Arg was not observed in approximately 3,700 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. CHEK2 Lys472Arg occurs at a position that is not conserved and is located within the protein kinase domain (Desrichard 2011, Roeb 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether CHEK2 Lys472Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000537431 SCV000633133 uncertain significance Familial cancer of breast 2017-03-13 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 472 of the CHEK2 protein (p.Lys472Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CHEK2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
GeneKor MSA RCV000708695 SCV000821991 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Color RCV000708695 SCV000910219 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-13 criteria provided, single submitter clinical testing

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