Submissions for variant NM_007194.4(CHEK2):c.1450C>A (p.Pro484Thr)

gnomAD frequency: 0.00001  dbSNP: rs548850521

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212467	SCV000210992	uncertain significance	not provided	2014-07-08	criteria provided, single submitter	clinical testing	This variant is denoted CHEK2 c.1450C>A at the cDNA level, p.Pro484Thr (P484T) at the protein level, and results in the change of a Proline to a Threonine (CCG>ACG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Pro484Thr 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 Proline and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CHEK2 Pro484Thr occurs at a position that is highly conserved across species and is located within the protein kinase domain (Roeb 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether CHEK2 Pro484Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000160439	SCV000217993	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-21	criteria provided, single submitter	clinical testing	The p.P484T variant (also known as c.1450C>A), located in coding exon 12 of the CHEK2 gene, results from a C to A substitution at nucleotide position 1450. The proline at codon 484 is replaced by threonine, an amino acid with highly similar properties. This alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). 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.
Invitae	RCV000538234	SCV000633136	uncertain significance	Familial cancer of breast	2023-10-28	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 484 of the CHEK2 protein (p.Pro484Thr). This variant is present in population databases (rs548850521, gnomAD 0.0009%). 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: 182439). 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 tolerated. Experimental studies have shown that this missense change does not substantially affect CHEK2 function (PMID: 30851065). 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	RCV000160439	SCV000913572	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-22	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 484 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). A functional study has shown the mutant protein to exhibit normal CHEK2 protein function in a DNA damage repair assay in yeast (PMID: 30851065). This variant has been reported in an individual affected with breast cancer (PMID: 33471991). This variant has been identified in 1/233782 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.
Sema4, Sema4	RCV000160439	SCV002537377	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-23	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV000538234	SCV002580752	uncertain significance	Familial cancer of breast	2022-01-25	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000212467	SCV001741339	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000212467	SCV001953105	uncertain significance	not provided		no assertion criteria provided	clinical testing