Submissions for variant NM_007194.4(CHEK2):c.1427C>A (p.Thr476Lys)

dbSNP: rs142763740

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000570223	SCV000675997	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-14	criteria provided, single submitter	clinical testing	The p.T476K variant (also known as c.1427C>A), located in coding exon 12 of the CHEK2 gene, results from a C to A substitution at nucleotide position 1427. The threonine at codon 476 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). A yeast based complementation assay demonstrated that this alteration produced intermediate growth compared to wild-type and negative controls (Roeb, Higgens, and King. Hum. Mol. Genet. 2012 Jun; 21(12):2738-44). In addition, functional assays of CHEK2 kinase activity demonstrated that this alteration results in partially reduced activity (Wu X et al. Hum. Mutat. 2006 Aug; 27(8):742-7). 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	RCV000570223	SCV000689654	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-20	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with lysine at codon 476 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). Functional studies demonstrated this variant had intermediate activity in a yeast DNA damage response assay (PMID: 22419737) but similar kinase activity to wild-type (PMID: 16835864). This variant has been observed in a prostate tumor sample (PMID: 16835864) and an individual referred for genetic testing (PMID: 31159747). 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.
GeneKor MSA	RCV000570223	SCV000821993	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Invitae	RCV000698621	SCV000827298	uncertain significance	Familial cancer of breast	2022-10-19	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 476 of the CHEK2 protein (p.Thr476Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with prostate cancer (PMID: 16835864). ClinVar contains an entry for this variant (Variation ID: 486833). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CHEK2 function (PMID: 16835864, 22419737). 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.
Sema4, Sema4	RCV000570223	SCV002537373	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-19	criteria provided, single submitter	curation