ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.973A>G (p.Lys325Glu)

dbSNP: rs587780193
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000512871 SCV000568941 uncertain significance not provided 2020-10-20 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
CeGaT Center for Human Genetics Tuebingen RCV000512871 SCV000609073 uncertain significance not provided 2017-05-01 criteria provided, single submitter clinical testing
Invitae RCV000528645 SCV000633238 uncertain significance Familial cancer of breast 2024-01-04 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 325 of the CHEK2 protein (p.Lys325Glu). 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: 420222). 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.
Ambry Genetics RCV000574986 SCV000665157 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-03 criteria provided, single submitter clinical testing The p.K325E variant (also known as c.973A>G), located in coding exon 8 of the CHEK2 gene, results from an A to G substitution at nucleotide position 973. The lysine at codon 325 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is highly 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 RCV000574986 SCV000684702 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-24 criteria provided, single submitter clinical testing This missense variant replaces lysine with glutamic acid at codon 325 of the CHEK2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 2/53461 controls (PMID: 33471991). 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.
Sema4, Sema4 RCV000574986 SCV002537661 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-17 criteria provided, single submitter curation

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