ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.482A>G (p.Glu161Gly)

dbSNP: rs730881683
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160425 SCV000210962 uncertain significance not provided 2022-08-23 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 colon cancer (DeRycke et al., 2017); This variant is associated with the following publications: (PMID: 22419737, 19782031, 31937788, 28944238)
Invitae RCV000467058 SCV000550465 uncertain significance Familial cancer of breast 2022-11-13 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 161 of the CHEK2 protein (p.Glu161Gly). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 182426). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. This variant is present in population databases (rs730881683, gnomAD 0.0009%).
Ambry Genetics RCV000571351 SCV000661774 uncertain significance Hereditary cancer-predisposing syndrome 2022-04-11 criteria provided, single submitter clinical testing The p.E161G variant (also known as c.482A>G), located in coding exon 3 of the CHEK2 gene, results from an A to G substitution at nucleotide position 482. The glutamic acid at codon 161 is replaced by glycine, an amino acid with similar properties. This variant has been reported in one control patient in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This variant was detected in a study of 1231 colorectal cancer patients and 93 controls (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). This variant was also identified in a cohort of children undergoing sequencing for intellectual disability with or without additional findings (Chirita-Emandi A et al. Sci Rep, 2020 01;10:223). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000571351 SCV000684650 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780180 SCV000917233 uncertain significance not specified 2017-10-06 criteria provided, single submitter clinical testing Variant summary: The CHEK2 c.482A>G (p.Glu161Gly) variant located in the SMAD/FHA domain superfamily (via InterPro) involves the alteration of a conserved nucleotide and 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). However, these predictions have yet to be functionally assessed. This variant was found in 1/246202 control chromosomes (gnomAD) at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0000284). In addition, multiple clinical diagnostic laboratories classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Baylor Genetics RCV000467058 SCV004215835 uncertain significance Familial cancer of breast 2023-10-31 criteria provided, single submitter clinical testing

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