Submissions for variant NM_007194.4(CHEK2):c.451G>T (p.Gly151Cys)

gnomAD frequency: 0.00001  dbSNP: rs587781377

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129197	SCV000183938	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	The p.G151C variant (also known as c.451G>T), located in coding exon 3 of the CHEK2 gene, results from a G to T substitution at nucleotide position 451. The glycine at codon 151 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 May;40:631-648). This alteration was seen in 1/732 breast cancer patients, 0/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). 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.
GeneDx	RCV000212420	SCV000210960	uncertain significance	not provided	2022-04-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate no damaging effect: growth rate comparable to wild-type in a yeast-based assay (Delimitsou 2019); This variant is associated with the following publications: (PMID: 19782031, 22419737, 30851065)
Invitae	RCV000536468	SCV000633190	uncertain significance	Familial cancer of breast	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 151 of the CHEK2 protein (p.Gly151Cys). This variant is present in population databases (rs587781377, gnomAD no frequency). 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: 140928). 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.
Color Diagnostics, LLC DBA Color Health	RCV000129197	SCV000684642	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with cysteine at codon 151 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). A functional study has reported the mutant protein to be functional in DNA damage response assay in yeast (PMID: 30851065). This variant has been reported in an individual affected with lung cancer (PMID: 29866652). This variant has been identified in 1/251322 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.
Sema4, Sema4	RCV000129197	SCV002537437	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-06	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149888	SCV003838789	uncertain significance	Breast and/or ovarian cancer	2021-08-11	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000536468	SCV004015281	uncertain significance	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with cysteine at codon 151 of the CHEK2 protein (p.Gly151Cys). This variant has not been reported in the literature in individuals with a CHEK2-related disease. ClinVar contains an entry for this variant (Variation ID: 140928) with 4 submissions, all of which describe this variant as of uncertain significance. Pathogenic computational verdict based on 10 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationAssessor, MutationTaster and SIFT vs 2 benign predictions from EIGEN and PrimateAI and the glycine residue is highly conserved. In summary, this variant has uncertain impact on CHEK2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212420	SCV004221744	uncertain significance	not provided	2023-04-07	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/251322 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with breast cancer (PMID: 32658311 (2021)), as well as in the somatic state in an individual with lung cancer (PMID: 29866652 (2018)). One yeast-based functional assay demonstrated that this variant had a growth rate similar to the positive control, suggesting a non-damaging effect (PMID: 30851065 (2019)). Additional studies are needed to determine the overall impact of this variant on gene and gene product. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.