Submissions for variant NM_007194.4(CHEK2):c.354C>G (p.Asp118Glu)

dbSNP: rs757340619

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220471	SCV000277364	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-01	criteria provided, single submitter	clinical testing	The p.D118E variant (also known as c.354C>G), located in coding exon 2 of the CHEK2 gene, results from a C to G substitution at nucleotide position 354. The aspartic acid at codon 118 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration was not detected in 6385 epithelial ovarian cancer cases and was identified in 1/6115 controls of broad European ancestry(Song H et al. J Med Genet, 2021 05;58:305-313). 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.
GeneDx	RCV000220593	SCV000279459	uncertain significance	not provided	2019-01-18	criteria provided, single submitter	clinical testing	This variant is denoted CHEK2 c.354C>G at the cDNA level, p.Asp118Glu (D118E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAC>GAG). This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. CHEK2 Asp118Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Aspartic Acid and Glutamic Acid share similar properties, this is considered a conservative amino acid substitution. CHEK2 Asp118Glu occurs at a position that is conserved across species and is located in the forkhead associated (FHA) 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 Asp118Glu is pathogenic or benign.
Invitae	RCV000635813	SCV000757236	uncertain significance	Familial cancer of breast	2023-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 118 of the CHEK2 protein (p.Asp118Glu). 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: 233065). 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.
Color Diagnostics, LLC DBA Color Health	RCV000220471	SCV004361401	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-30	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glutamic acid at codon 118 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 not been reported in individuals affected with hereditary cancer in the literature. 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.