Submissions for variant NM_007194.4(CHEK2):c.500G>A (p.Gly167Glu)

gnomAD frequency: 0.00002  dbSNP: rs144850845

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000116021	SCV000149930	uncertain significance	not provided	2023-03-28	criteria provided, single submitter	clinical testing	Observed in individuals with male breast cancer or pancreatic cancer (Rizzolo et al., 2019; Rapposelli et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.629G>A p.Gly210Glu; This variant is associated with the following publications: (PMID: 25503501, 22419737, 25452411, 15095295, 27616075, 26976419, 19782031, 30613976, 34034685, 31398194)
Invitae	RCV000474336	SCV000550520	uncertain significance	Familial cancer of breast	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 167 of the CHEK2 protein (p.Gly167Glu). This variant is present in population databases (rs144850845, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 30613976). This variant is also known as Gly210Glu. ClinVar contains an entry for this variant (Variation ID: 128078). 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 disruptive. This variant disrupts the p.Gly167 amino acid residue in CHEK2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15095295, 22419737, 25452411, 25503501, 26976419, 27616075; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Ambry Genetics	RCV000565735	SCV000661727	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-03	criteria provided, single submitter	clinical testing	The p.G167E variant (also known as c.500G>A), located in coding exon 3 of the CHEK2 gene, results from a G to A substitution at nucleotide position 500. The glycine at codon 167 is replaced by glutamic acid, an amino acid with similar properties. This alteration was detected in 1/60 Italian individuals with a personal diagnosis of pancreatic cancer (Rapposelli IG et al. BMC Cancer, 2021 May;21:611). 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.
Color Diagnostics, LLC DBA Color Health	RCV000565735	SCV000684651	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-04	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 167 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. Another variant at this position (p.Gly167Arg) has been classified as likely pathogenic (ClinVar Variation ID: 142524), suggesting this position may be important for function. This variant has been identified in 2/251428 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.