Submissions for variant NM_007194.4(CHEK2):c.851G>A (p.Cys284Tyr)

gnomAD frequency: 0.00001  dbSNP: rs876658150

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218814	SCV000273007	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-19	criteria provided, single submitter	clinical testing	The p.C284Y variant (also known as c.851G>A), located in coding exon 7 of the CHEK2 gene, results from a G to A substitution at nucleotide position 851. The cysteine at codon 284 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). In addition, it has been reported in at least once in a cohort of African American women that included 37 individuals affected with breast cancer and 51 family members (McDonald JT. PLoS One. 2022 Oct;17(10):e0273835). One study has reported that this alteration resulted in increased resistance to doxorubicin and impaired phosphorylation of CHK2 in a CRISPR-based gene-editing screen performed in a human breast cell line (Cuella-Martin R. Cell. 2021 Feb;184(4):1081-1097.e19). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000234274	SCV000289712	uncertain significance	Familial cancer of breast	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 284 of the CHEK2 protein (p.Cys284Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 36315513). This missense change has been observed to co-occur in individuals with a different variant in CHEK2 that has been determined to be pathogenic (Invitae), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 229700). 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. 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	RCV000234274	SCV000784846	uncertain significance	Familial cancer of breast	2016-12-27	criteria provided, single submitter	clinical testing
Mendelics	RCV000234274	SCV000839478	uncertain significance	Familial cancer of breast	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000218814	SCV001348054	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-27	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 284 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 hereditary cancer 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.
Sema4, Sema4	RCV000218814	SCV002537649	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-20	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465568	SCV002761104	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
GeneDx	RCV003153494	SCV003842500	uncertain significance	not provided	2023-03-16	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; Identified in individuals with breast cancer (Dorling et al., 2021); Published functional studies suggest this variant reduces protein production/phosphorylation and confers a growth advantage (Cuella-Martin et al., 2021); This variant is associated with the following publications: (PMID: 22419737, 19782031, 33471991, 33606978)
Myriad Genetics, Inc.	RCV000234274	SCV004020096	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.