Submissions for variant NM_007194.4(CHEK2):c.59A>G (p.Gln20Arg)

gnomAD frequency: 0.00001  dbSNP: rs753257724

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218111	SCV000276905	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-30	criteria provided, single submitter	clinical testing	The p.Q20R variant (also known as c.59A>G), located in coding exon 1 of the CHEK2 gene, results from an A to G substitution at nucleotide position 59. The glutamine at codon 20 is replaced by arginine, an amino acid with highly similar properties. 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.
Invitae	RCV000476107	SCV000550469	uncertain significance	Familial cancer of breast	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 20 of the CHEK2 protein (p.Gln20Arg). This variant is present in population databases (rs753257724, 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: 232706). 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.
GeneDx	RCV000759044	SCV000566634	uncertain significance	not provided	2020-03-26	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Absent from breast cancer cases but observed in control populations (Momozawa 2018); This variant is associated with the following publications: (PMID: 30287823)
Color Diagnostics, LLC DBA Color Health	RCV000218111	SCV000684671	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-10	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 20 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 been identified in 2/247598 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759044	SCV000888116	uncertain significance	not provided	2018-05-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781295	SCV000919214	uncertain significance	not specified	2017-09-19	criteria provided, single submitter	clinical testing	Variant summary: The c.59A>G (p.Gln20Arg) in CHEK2 gene is a missense variant involves a non-conserved nucleotide and 2/4 in silico tools predict benign outcome, however no functional studies supporting these predictions were published at the time of evaluation. The variant is located within the SQ/TQ cluster domain, although the functional impact of this change on protein remains unclear. The c.7984A>G is present in the control population datasets of ExAC and gnomAD at a low frequency of 0.000008 (2/ 242298 chrs tested), which does not exceed the maximum expected allele frequency for a pathogenic variant of 0.000028. To our knowledge, the variant has not been reported in affected individuals via published reports, but is cited as VUS by reputable databases/clinical laboratories. Taken together, the variant was classified as VUS, until new information becomes available.