Submissions for variant NM_007194.4(CHEK2):c.1556G>A (p.Arg519Gln)

dbSNP: rs587780180

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212475	SCV000149915	uncertain significance	not provided	2023-06-15	criteria provided, single submitter	clinical testing	Observed in individuals with breast and colorectal cancer (Tung 2015, Yurgelun 2017, Hauke 2018); Not observed at a significant frequency in large population cohorts (gnomAD); Published functional studies are inconclusive: intermediate growth after DNA damage (Delimitsou 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24879340, 28135145, 29872864, 25186627, 29522266, 22419737, 30851065)
Ambry Genetics	RCV000116006	SCV000213913	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-13	criteria provided, single submitter	clinical testing	The p.R519Q variant (also known as c.1556G>A), located in coding exon 14 of the CHEK2 gene, results from a G to A substitution at nucleotide position 1556. The arginine at codon 519 is replaced by glutamine, an amino acid with highly similar properties. This variant was observed in an individual with early onset-breast cancer amongst a cohort of 1781 non-Ashkenazi Jewish individuals undergoing BRCA1/2 gene testing based on a personal history of breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33). In addition, this alteration has 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), and in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This variant has also been reported in an individual affected with colorectal cancer (Yurgelun MB et al. J Clin Oncol, 2017 Apr;35:1086-1095). One study reports that this alteration behaved as semi-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 not well conserved in available vertebrate species, and glutamine is the reference amino acid in other 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.
Invitae	RCV000227687	SCV000289667	uncertain significance	Familial cancer of breast	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 519 of the CHEK2 protein (p.Arg519Gln). 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 missense change has been observed in individual(s) with breast cancer and/or colorectal cancer (PMID: 25186627, 28135145, 29522266). ClinVar contains an entry for this variant (Variation ID: 128065). 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 glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on 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	RCV000116006	SCV000910841	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-12	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 519 of the CHEK2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported this variant to cause partial loss of CHEK2 function in yeast complementation assay (PMID: 30851065). This variant has been reported in individuals affected with breast or colorectal cancer (PMID: 25186627, 28135145) and in a family suspected of having hereditary breast and ovarian cancer syndrome (PMID: 29522266). This variant has been identified in 7/233042 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212475	SCV001134162	uncertain significance	not provided	2022-08-15	criteria provided, single submitter	clinical testing
Division of Medical Genetics, University of Washington	RCV000227687	SCV001424782	uncertain significance	Familial cancer of breast	2019-02-01	criteria provided, single submitter	clinical testing	To our knowledge, this sequence variant has not been previously reported in the literature in individuals with cancer. This variant has an overall allele frequency of 0.0002 in the Broad Institute ExAC Browser (http://exac.broadinstitute.org/). Thus, it is unknown at this time whether this variant increases cancer risk.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265609	SCV002548439	uncertain significance	not specified	2022-05-27	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.1556G>A (p.Arg519Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3e-05 in 233042 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1556G>A, has been reported in the literature inas a VUS in settings of multigene panel testing among individuals affected with breast and colorectal cancers (example Tung_2015, Yurgelun_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A yeast-based functional assay found that the variant had an intermediate effect on protein function based on the ability to repair DNA after chemically induced damage (Delimitsou_2019). However, this does not allow any strong conclusions about the variant effect. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV000212475	SCV003832007	uncertain significance	not provided	2019-05-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000227687	SCV004217529	uncertain significance	Familial cancer of breast	2023-09-29	criteria provided, single submitter	clinical testing