Submissions for variant NM_007194.4(CHEK2):c.8G>T (p.Arg3Leu)

dbSNP: rs779607427

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000459842	SCV000550484	uncertain significance	Familial cancer of breast	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 3 of the CHEK2 protein (p.Arg3Leu). 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: 410029). 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	RCV000573624	SCV000666382	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-13	criteria provided, single submitter	clinical testing	The p.R3L variant (also known as c.8G>T), located in coding exon 1 of the CHEK2 gene, results from a G to T substitution at nucleotide position 8. The arginine at codon 3 is replaced by leucine, an amino acid with dissimilar properties. In one study of 57 patients with cutaneous melanoma and a history of two or more additional non-cutaneous primary cancers, this variant was seen in 0/57 cases but was reported in 1/1358 unrelated, non-cancer controls (Pritchard AL et al. PLoS ONE, 2018 Apr;13:e0194098). 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.
Illumina Laboratory Services, Illumina	RCV001145231	SCV001305881	uncertain significance	CHEK2-Related Cancer Susceptibility	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genetic Services Laboratory, University of Chicago	RCV001821280	SCV002066857	uncertain significance	not specified	2021-02-16	criteria provided, single submitter	clinical testing
GeneDx	RCV003441879	SCV004170299	uncertain significance	not provided	2023-04-07	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; Observed in an individual with melanoma (Pritchard et al., 2018); This variant is associated with the following publications: (PMID: 29641532)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355873	SCV001550885	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CHEK2 p.Arg3Leu variant was not identified in the literature nor was it identified in the dbSNP database. The variant was identified in ClinVar (classified as uncertain significance by Invitae and Ambry Genetics). The variant was not identified in the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The p.Arg3 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.