ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1543C>A (p.Pro515Thr)

dbSNP: rs1399879170
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000776765 SCV000912409 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-29 criteria provided, single submitter clinical testing This missense variant replaces proline with threonine at codon 515 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 1/231812 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 RCV001856133 SCV002181458 uncertain significance Familial cancer of breast 2023-11-09 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 515 of the CHEK2 protein (p.Pro515Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 630769). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 RCV000776765 SCV002706267 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-21 criteria provided, single submitter clinical testing The p.P515T variant (also known as c.1543C>A), located in coding exon 14 of the CHEK2 gene, results from a C to A substitution at nucleotide position 1543. This variant impacts the first base pair of coding exon 14. The proline at codon 515 is replaced by threonine, an amino acid with highly similar properties. This amino acid position is not 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.

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