Submissions for variant NM_007194.4(CHEK2):c.855C>G (p.Ile285Met)

gnomAD frequency: 0.00001  dbSNP: rs756692505

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220847	SCV000274321	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-19	criteria provided, single submitter	clinical testing	The p.I285M variant (also known as c.855C>G), located in coding exon 7 of the CHEK2 gene, results from a C to G substitution at nucleotide position 855. The isoleucine at codon 285 is replaced by methionine, an amino acid with highly similar properties. This alteration was reported as functional in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Stolarova L et al. Clin Cancer Res, 2023 Aug;29:3037-3050). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV000215612	SCV000278923	uncertain significance	not provided	2024-02-22	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in individuals referred for multi-gene hereditary cancer panel testing (PMID: 27720647); This variant is associated with the following publications: (PMID: 22419737, 19782031, 27720647, 36922933)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526256	SCV000633221	uncertain significance	Familial cancer of breast	2023-09-23	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 285 of the CHEK2 protein (p.Ile285Met). This variant is present in population databases (rs756692505, gnomAD 0.001%). 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: 230685). 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	RCV000220847	SCV001355159	uncertain significance	Hereditary cancer-predisposing syndrome	2020-04-17	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 285 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. 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.
Baylor Genetics	RCV000526256	SCV004217608	uncertain significance	Familial cancer of breast	2024-03-24	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004737349	SCV005355937	uncertain significance	CHEK2-related disorder	2024-07-09	no assertion criteria provided	clinical testing	The CHEK2 c.855C>G variant is predicted to result in the amino acid substitution p.Ile285Met. This variant has been reported in a study on CHEK2-complementation in human RPE1-CHEK2-knockout cells (Table S1. Stolarova et al 2023. PubMed ID: 37449874.) This variant is reported in 0.0010% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/230685/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.