Submissions for variant NM_007194.4(CHEK2):c.1383C>G (p.Asp461Glu)

gnomAD frequency: 0.00002  dbSNP: rs1060502702

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000467590	SCV000550488	uncertain significance	Familial cancer of breast	2023-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 461 of the CHEK2 protein (p.Asp461Glu). This variant is present in population databases (no rsID available, gnomAD 0.002%). 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: 410033). 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.
Ambry Genetics	RCV000569776	SCV000661719	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-09	criteria provided, single submitter	clinical testing	The p.D461E variant (also known as c.1383C>G), located in coding exon 12 of the CHEK2 gene, results from a C to G substitution at nucleotide position 1383. The aspartic acid at codon 461 is replaced by glutamic acid, an amino acid with highly similar properties. This variant has been reported in individuals with breast cancer (Decker B et al. J Med Genet, 2017 11;54:732-741; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879), in a cohort of 149 individuals from either families with an accumulation of colorectal cancers or families with only one sporadic case of very early onset colorectal cancer (Djursby M et al. Front Genet, 2020 Sep;11:566266), and in a pediatric patient with precursor T-ALL (Byrjalsen A et al. PLoS Genet, 2020 12;16:e1009231). This alteration behaved as semi-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588837	SCV000698773	uncertain significance	not provided	2016-12-22	criteria provided, single submitter	clinical testing	Variant summary: The CHEK2 c.1383C>G (p.Asp461Glu) variant located in the protein kinase-like domain (via InterPro) causes a missense change involving a conserved nucleotide, which 2/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP), nor has it been, to our knowledge, reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "variant of uncertain significance (VUS)."
Color Diagnostics, LLC DBA Color Health	RCV000569776	SCV000904247	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-14	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glutamic acid at codon 461 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). A functional study in yeast has reported that this variant has an intermediate impact on DNA damage repair activity of the CHEK2 protein (PMID 30851065). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/265144 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003320467	SCV004024667	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358131	SCV001553790	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CHEK2 p.Asp461Glu variant was not identified in the literature, nor was it identified in dbSNP, Cosmic, MutDB, or the Zhejiang University Database. The variant was identified in ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, Laboratory Corporation of America). The variant was also identified in control databases in 3 of 260120 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: “Other” in 1 of 6278 chromosomes (freq: 0.0002), and European in 2 of 121992 chromosomes (freq: 0.00002); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Asp461 residue is conserved in mammals but not in more distantly related organisms, however, four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.