Submissions for variant NM_007194.4(CHEK2):c.1076A>G (p.Glu359Gly)

gnomAD frequency: 0.00001  dbSNP: rs760449049

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222729	SCV000278103	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-27	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000482650	SCV000566258	uncertain significance	not provided	2023-04-14	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 individuals with an individual with a personal history of a Lynch syndrome-related cancer and/or polyps (Yurgelun et al., 2015); This variant is associated with the following publications: (PMID: 25980754, 28576879, 22419737, 19782031, 28779002, 30262796)
Color Diagnostics, LLC DBA Color Health	RCV000222729	SCV000689628	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-10	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000635710	SCV000757131	uncertain significance	Familial cancer of breast	2024-01-10	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 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.
Genetic Services Laboratory, University of Chicago	RCV001818540	SCV002065798	uncertain significance	not specified	2021-11-29	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000635710	SCV004217610	uncertain significance	Familial cancer of breast	2023-08-04	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000482650	SCV001553264	uncertain significance	not provided		no assertion criteria provided	clinical testing	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.