Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000160424 | SCV000210961 | uncertain significance | not provided | 2014-08-25 | criteria provided, single submitter | clinical testing | This variant is denoted CHEK2 c.458A>G at the cDNA level, p.Lys153Arg (K153R) at the protein level, and results in the change of a Lysine to an Arginine (AAA>AGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Lys153Arg was not observed in approximately 6,500 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 Lys153Arg occurs at a position that is highly conserved across species and is located in within the FHA domain (Roeb 2012, UniProt). 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 Lys153Arg is pathogenic or benign. We consider it to be a variant of uncertain significance. |
Invitae | RCV002515114 | SCV003349133 | uncertain significance | Familial cancer of breast | 2022-05-03 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 153 of the CHEK2 protein (p.Lys153Arg). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 182425). 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. 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. |