22-28725004-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_007194.4(CHEK2):c.565A>G(p.Ile189Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,942 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_007194.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152104Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251418Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135898
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461838Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727224
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152104Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74298
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:2
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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. -
Hereditary cancer-predisposing syndrome Uncertain:2
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. 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) while the other reported it as functional (PMID: 30851065). The variant was also functional in KAP1 in vitro kinase assays and CHK2 autophosphorylation assays (PMID: 37449874). 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. -
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 variant was also 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 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. Based on the available evidence, the clinical significance of this variant remains unclear. -
not provided Uncertain:1Other:1
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) -
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. -
not specified Uncertain:1
Variant summary: CHEK2 c.565A>G (p.Ile189Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251418 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.565A>G has been reported in the literature in individuals affected with breast or ovarian cancer (Roeb_2012, Frey_2017, Susswein_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Three publications report experimental evidence evaluating an impact on protein function, however, none of these studies allows convincing conclusions about the variant effect (Roeb_2012, Delimitsou_2019, Stolarova_2023). The following publications have been ascertained in the context of this evaluation (PMID: 30851065, 28495237, 22419737, 37449874, 26681312). ClinVar contains an entry for this variant (Variation ID: 128082). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Familial cancer of breast;C0346629:Colorectal cancer;C0376358:Malignant tumor of prostate;C0585442:Bone osteosarcoma;C5882668:Li-Fraumeni syndrome 2 Uncertain:1
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Familial prostate cancer Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at