ClinVar Genomic variation as it relates to human health

The p.E359G variant (also known as c.1076A>G), located in coding exon 9 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1076. The glutamic acid at codon 359 is replaced by glycine, an amino acid with similar properties. This alteration was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20). This alteration has also been reported in at least one breast cancer 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 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.

Observed in individuals with breast cancer or a Lynch syndrome-related cancer and/or polyps (PMID: 25980754, 37449874); Published functional studies demonstrate KAP1 phosphorylation and CHK2 auto-phosphorylation comparable to wild-type (PMID: 37449874); RNA studies demonstrate aberrant splicing resulting in both in-frame and out-of-frame transcripts (PMID: 38332730); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25980754, 28576879, 28779002, 30262796, 22419737, 19782031, 33471991, 35451682, 37449874, 38332730)

DNA sequence analysis of the CHEK2 gene demonstrated a sequence change, c.1076A>G, in exon 10 that results in an amino acid change, p.Glu359Gly. This sequence change has been described in the gnomAD database in two individuals which corresponds to a population frequency of 0.0018 % (dbSNP rs760449049). The p.Glu359Gly change affects a moderately conserved amino acid residue located in a domain of the CHEK2 protein that is known to be functional. The p.Glu359Gly substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with CHEK2-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Glu359Gly change remains unknown at this time.

This missense variant replaces glutamic acid with glycine at codon 359 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 been reported in an individual suspected of having Lynch syndrome (PMID: 25980754) and in two unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000369). This variant has been identified in 2/251266 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.

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 359 of the CHEK2 protein (p.Glu359Gly). This variant is present in population databases (rs760449049, gnomAD 0.002%). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 233678). 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.

Variant summary: CHEK2 c.1076A>G (p.Glu359Gly) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251266 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1076A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome as well as healthy controls (e.g., Yurgelun_2015, Decker_2017, Stolarova_2023). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on kinase activity (e.g., Stolarova_2023). The following publications have been ascertained in the context of this evaluation (PMID: 37449874, 25980754, 28779002). ClinVar contains an entry for this variant (Variation ID: 233678). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and nonpolar, at codon 359 of the CHEK2 protein (p.Glu359Gly)This amino acid position is poorly conserved (PhyloP=3.45) . This variant is present in population databases (rs760449049, gnomAD 0.002%). This missense change has been observed in individual(s) with Lynch syndrome PMID: 25980754, 28576879, 28779002, 30262796, 22419737, 19782031, 33471991, 35451682, 37449874, 38332730). ClinVar contains an entry for this variant (Variation ID: 233678). In addition, this alteration is predicted to be tolerated by in silico analysis. 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.Pathogenic/likely pathogenic mutations in the CHEK2 gene cause susceptibility to breast cancer (OMIM# 114480).

The CHEK2 p.Glu359Gly variant was identified in 1 of 2520 proband chromosomes (frequency: 0.0004) from individuals or families with Lynch syndrome (Yurgelun 2015). The variant was also identified in dbSNP (ID: rs760449049) as "With Uncertain significance allele" and ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics, and Color). The variant was not identified in the Cosmic, MutDB, Zhejiang University database, the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The p.Glu359 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.