Submissions for variant NM_007194.4(CHEK2):c.949A>G (p.Lys317Glu)

gnomAD frequency: 0.00001  dbSNP: rs587782416

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131462	SCV000186446	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-13	criteria provided, single submitter	clinical testing	The p.K317E variant (also known as c.949A>G), located in coding exon 8 of the CHEK2 gene, results from an A to G substitution at nucleotide position 949. The lysine at codon 317 is replaced by glutamic acid, an amino acid with 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.
Invitae	RCV000226721	SCV000289718	uncertain significance	Familial cancer of breast	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 317 of the CHEK2 protein (p.Lys317Glu). This variant is present in population databases (rs587782416, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer and colorectal cancer (PMID: 28135145, 34326862). ClinVar contains an entry for this variant (Variation ID: 142376). 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. 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.
GeneDx	RCV000486217	SCV000570355	uncertain significance	not provided	2016-05-16	criteria provided, single submitter	clinical testing	This variant is denoted CHEK2 c.949A>G at the cDNA level, p.Lys317Glu (K317E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Lys317Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CHEK2 Lys317Glu occurs at a position that is not conserved and is located within the protein kinase domain (Desrichard 2011, Roeb 2012). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether CHEK2 Lys317Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000131462	SCV000684700	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 317 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 been reported in an individual affected with colorectal cancer (PMID: 28135145). This variant has also been identified in 2/251486 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.
Counsyl	RCV000226721	SCV000786075	uncertain significance	Familial cancer of breast	2018-02-22	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798451	SCV002043414	uncertain significance	Breast and/or ovarian cancer	2023-04-25	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000226721	SCV004020169	uncertain significance	Familial cancer of breast	2023-03-09	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.