Submissions for variant NM_007194.4(CHEK2):c.787G>C (p.Glu263Gln)

gnomAD frequency: 0.00001  dbSNP: rs730881686

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160428	SCV000210974	uncertain significance	not provided	2017-08-29	criteria provided, single submitter	clinical testing	This variant is denoted CHEK2 c.787G>C at the cDNA level, p.Glu263Gln (E263Q) at the protein level, and results in the change of a Glutamic Acid to a Glutamine (GAG>CAG). This variant has been reported in at least one woman with a history of breast cancer (Tung 2016). CHEK2 Glu263Gln was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamic Acid and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. CHEK2 Glu263Gln occurs at a position that is conserved across species and is located in the protein kinase domain (Desrichard 2011, Roeb 2012). In addition, 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 Glu263Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000575022	SCV000661703	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-01	criteria provided, single submitter	clinical testing	The p.E263Q variant (also known as c.787G>C), located in coding exon 5 of the CHEK2 gene, results from a G to C substitution at nucleotide position 787. The glutamic acid at codon 263 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a cohort of 488 patients with stages I to III breast cancer who were tested with a 25-gene panel test (Tung N et al. J. Clin. Oncol., 2016 May;34:1460-8). This alteration has also been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). 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 well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000575022	SCV000913588	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-01	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 263 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). Experimental studies in a yeast DNA damage response assay demonstrate normal repair activity (PMID: 30851065). This variant has been reported in one individual affected with breast cancer in the literature (PMID: 26976419). This variant has been identified in 2/251158 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	RCV000793724	SCV000933091	uncertain significance	Familial cancer of breast	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 263 of the CHEK2 protein (p.Glu263Gln). This variant is present in population databases (rs730881686, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 182429). 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.