Submissions for variant NM_007194.4(CHEK2):c.565A>G (p.Ile189Val)

gnomAD frequency: 0.00001  dbSNP: rs587780185

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212429	SCV000149935	uncertain significance	not provided	2023-07-11	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; Observed in individuals with breast, ovarian, and other cancers, and did not show loss of heterozygosity in a sarcoma sample (Schrader et al., 2016; Frey et al., 2017; Stafford et al., 2017); Published functional studies are conflicting with respect to DNA damage response activity (Roeb et al., 2012; Delimitsou et al., 2019); This variant is associated with the following publications: (PMID: 26681312, 26556299, 28495237, 22419737, 28301460, 30851065, 28591191, 19782031)
Ambry Genetics	RCV000116026	SCV000215380	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-26	criteria provided, single submitter	clinical testing	The p.I189V variant (also known as c.565A>G), located in coding exon 3 of the CHEK2 gene, results from an A to G substitution at nucleotide position 565. The isoleucine at codon 189 is replaced by valine, an amino acid with highly similar properties. This alteration is located in the FHA domain and was characterized as damaging based on a yeast-based assay to assess in vivo CHEK2-mediated response to DNA damage (Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44). However, this alteration behaved as functional in a different in vivo yeast-based growth assay (Delimitsou A et al. Hum. Mutat., 2019 05;40:631-648). This alteration was detected in two patients who underwent multi-gene panel testing, both of whom had early-onset breast cancer and a family history of colon cancer (Frey MK et al. Gynecol Oncol. 2017 May 8). It has also been identified in an individual with soft tissue sarcoma who also carried a germline BRCA2 mutation (Schrader K et al. JAMA Oncol 2016 Jan;2(1):104-11). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230801	SCV000289691	uncertain significance	Familial cancer of breast	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 189 of the CHEK2 protein (p.Ile189Val). This variant is present in population databases (rs587780185, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer and ovarian cancer and soft tissue sarcoma and breast and colon cancer (PMID: 22419737, 26556299, 28495237, 28591191). This variant is also known as I232V. ClinVar contains an entry for this variant (Variation ID: 128082). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 22419737, 30851065). 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	RCV000116026	SCV000689696	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-31	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 189 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). Two yeast-based DNA damage response assays have shown different results for the impact of this variant on protein function. One showed the variant to be non-functional (PMID: 22419737) and the other showed functional (PMID: 30851065). This variant has been reported in individuals affected with breast cancer (PMID: 22419737, 28495237), colon cancer (PMID: 22419737), soft tissue sarcoma (PMID: 26556299), and ovarian cancer (PMID: 28591191). This variant has also been identified in 1/251418 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.
Fulgent Genetics, Fulgent Genetics	RCV002483188	SCV002790909	uncertain significance	Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate; Colorectal cancer	2022-01-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000230801	SCV004217607	uncertain significance	Familial cancer of breast	2023-08-05	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV000212429	SCV002075256	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 03-09-2020 by Lab or GTR ID 1197. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.