Submissions for variant NM_007194.4(CHEK2):c.1228T>G (p.Cys410Gly)

dbSNP: rs1555913689

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000534212	SCV000633113	uncertain significance	Familial cancer of breast	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 410 of the CHEK2 protein (p.Cys410Gly). This variant is not present in population databases (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: 460793). 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.
Ambry Genetics	RCV000567460	SCV000661733	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-06	criteria provided, single submitter	clinical testing	The p.C410G variant (also known as c.1228T>G), located in coding exon 10 of the CHEK2 gene, results from a T to G substitution at nucleotide position 1228. The cysteine at codon 410 is replaced by glycine, an amino acid with highly dissimilar properties. This variant was reported in at least one individual from a cohort of 192 clinically suspicious of HBOC Spanish families without BRCA1/2 mutations (Bonache S et al. J Cancer Res Clin Oncol . 2018 Dec;144(12):2495-2513). This amino acid position is well 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.
Color Diagnostics, LLC DBA Color Health	RCV000567460	SCV000684571	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-26	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000534212	SCV005058397	uncertain significance	Familial cancer of breast	2023-12-24	criteria provided, single submitter	clinical testing
GeneDx	RCV004592563	SCV005079010	uncertain significance	not provided	2024-03-20	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 suggest a neutral effect: demonstrates auto-phosphorylation and kinase activity comparable to wild type (PMID: 37449874); This variant is associated with the following publications: (PMID: 19782031, 22419737, 30306255, 37449874)