Submissions for variant NM_007194.4(CHEK2):c.664A>G (p.Met222Val)

dbSNP: rs786203472

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166790	SCV000217604	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-05	criteria provided, single submitter	clinical testing	The p.M222V variant (also known as c.664A>G), located in coding exon 4 of the CHEK2 gene, results from an A to G substitution at nucleotide position 664. The methionine at codon 222 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in at least one subject 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 alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). This amino acid position is not well 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.
Invitae	RCV000204804	SCV000259844	uncertain significance	Familial cancer of breast	2023-11-29	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 222 of the CHEK2 protein (p.Met222Val). 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: 187101). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV000166790	SCV000913593	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-27	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 222 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). A functional study has shown that this variant does not adversely affect CHEK2 protein function in a complementation assay in yeast (PMID: 30851065). 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.
GeneDx	RCV002273967	SCV002559316	uncertain significance	not provided	2022-02-02	criteria provided, single submitter	clinical testing	Published functional studies demonstrate no damaging effect: cell growth and proliferation similar to wild-type in response to DNA damage (Delimitsou 2019); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22419737, 19782031, 30851065)