ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.934A>G (p.Lys312Glu)

gnomAD frequency: 0.00001  dbSNP: rs1064795532
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479455 SCV000571441 uncertain significance not provided 2016-08-21 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.934A>G at the cDNA level, p.Lys312Glu (K312E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Lys312Glu was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CHEK2 Lys312Glu occurs at a position where amino acids with properties similar to Lysine are tolerated across species and is located within the kinase domain (Desrichard 2011, Roeb 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether CHEK2 Lys312Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000559307 SCV000633235 uncertain significance Familial cancer of breast 2023-12-21 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 312 of the CHEK2 protein (p.Lys312Glu). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer and/or thyroid cancer (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 422065). 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 RCV000574009 SCV000669247 uncertain significance Hereditary cancer-predisposing syndrome 2022-09-23 criteria provided, single submitter clinical testing The p.K312E variant (also known as c.934A>G), located in coding exon 8 of the CHEK2 gene, results from an A to G substitution at nucleotide position 934. The lysine at codon 312 is replaced by glutamic acid, an amino acid with similar properties. This alteration was not observed in 53 unselected male breast cancer patients and was observed with an allele frequency of 0.0001 in 12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is poorly 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.
Color Diagnostics, LLC DBA Color Health RCV000574009 SCV001340915 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-24 criteria provided, single submitter clinical testing This missense variant replaces lysine with glutamic acid at codon 312 of the CHEK2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251418 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.
Sema4, Sema4 RCV000574009 SCV002537657 uncertain significance Hereditary cancer-predisposing syndrome 2021-05-18 criteria provided, single submitter curation
Baylor Genetics RCV000559307 SCV004217567 uncertain significance Familial cancer of breast 2023-09-07 criteria provided, single submitter clinical testing

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