Submissions for variant NM_007194.4(CHEK2):c.1591G>A (p.Glu531Lys)

gnomAD frequency: 0.00001  dbSNP: rs587781710

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214317	SCV000274889	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-20	criteria provided, single submitter	clinical testing	The p.E531K variant (also known as c.1591G>A), located in coding exon 14 of the CHEK2 gene, results from a G to A substitution at nucleotide position 1591. The glutamic acid at codon 531 is replaced by lysine, an amino acid with similar properties. This amino acid position is poorly 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.
Invitae	RCV000470987	SCV000550511	uncertain significance	Familial cancer of breast	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 531 of the CHEK2 protein (p.Glu531Lys). 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: 231134). 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 lysine 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.
Counsyl	RCV000470987	SCV000785737	uncertain significance	Familial cancer of breast	2017-11-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000214317	SCV001343031	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-06	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 531 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 CHEK2-related disorders in the literature. This variant has not been identified 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.
GeneDx	RCV001762482	SCV002008144	uncertain significance	not provided	2022-06-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230457	SCV003928339	uncertain significance	not specified	2023-04-18	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.1591G>A (p.Glu531Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.1e-05 in 233650 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1591G>A in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five 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.
Myriad Genetics, Inc.	RCV000470987	SCV004020126	uncertain significance	Familial cancer of breast	2023-03-08	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.