Submissions for variant NM_007194.4(CHEK2):c.1259G>A (p.Cys420Tyr)

dbSNP: rs578218280

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217861	SCV000278179	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-19	criteria provided, single submitter	clinical testing	The p.C420Y variant (also known as c.1259G>A), located in coding exon 10 of the CHEK2 gene, results from a G to A substitution at nucleotide position 1259. This nucleotide position is highly conserved in available vertebrate species. This change occurs in the last base pair of coding exon 10, which makes it likely to have some effect on normal mRNA splicing. RNA studies have demonstrated that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). This alteration also results in a cysteine to tyrosine change at codon 420, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the protein in silico prediction for this alteration is inconclusive. This alteration behaved as non-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat. 2019 05;40(5):631-648). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000766899	SCV000571729	uncertain significance	not provided	2016-09-20	criteria provided, single submitter	clinical testing	This variant is denoted CHEK2 c.1259G>A at the cDNA level, p.Cys420Tyr (C420Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGC>TAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Cys420Tyr was not observed at a significant allele frequency in 1000 Genomes. Since Cysteine and Tyrosine differ in polarity, charge, size, or other properties, this is considered a non-conservative amino acid substitution. CHEK2 Cys420Tyr alters a position that is conserved across species and is located in the kinase domain (Desrichard 2011, Roeb 2012). Protein-based in silico analyses predict that this variant is probably damaging to protein structure and function, and multiple splicing models predict that this variant may impact the nearby natural splice acceptor site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether CHEK2 Cys420Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago	RCV000485639	SCV000594115	uncertain significance	not specified	2016-12-06	criteria provided, single submitter	clinical testing
Invitae	RCV000539842	SCV000633116	uncertain significance	Familial cancer of breast	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change affects codon 420 of the CHEK2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CHEK2 protein. This variant also falls at the last nucleotide of exon 11, which is part of the consensus splice site for this exon. This variant is present in population databases (rs578218280, gnomAD 0.0009%). This variant has been observed in individual(s) with breast cancer (PMID: 32854451). This variant is also known as c.1388G>A (p.Cys463Tyr) . ClinVar contains an entry for this variant (Variation ID: 233743). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	RCV000217861	SCV000684576	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-31	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 420 of the CHEK2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. However, this variant causes a G>T nucleotide substitution at the last nucleotide of exon 11 of the CHEK2 gene, and splice site prediction tools suggest that this variant may impact RNA splicing. This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 32854451, 37449874). This variant has been identified in 1/249952 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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000539842	SCV004015277	uncertain significance	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine with tyrosine at codon 420 of the CHEK2 protein (p.Cys420Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant also falls at the last nucleotide of exon 11 of the CHEK2 coding sequence, which is part of the consensus splice site for this exon. This variant is not found in gnomAD genomes. This variant has not been reported in the literature in individuals with CHEK2-related disease. ClinVar contains an entry for this variant (Variation ID: 233743) with 5 submissions all of which describe it as of uncertain significance. In-silico predictions show pathogenic computational verdict based on 10 pathogenic predictions from BayesDel_addAF, DANN, EIGEN, FATHMMMKL, LIST-S2, M-CAP, MutationTaster, PrimateAI, SIFT and scSNV-Splicing vs 3 benign predictions from DEOGEN2, MVP and MutationAssessor. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098).. Therefore, it has been classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV000539842	SCV004217543	likely pathogenic	Familial cancer of breast	2023-09-21	criteria provided, single submitter	clinical testing