22-28695816-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong
The NM_007194.4(CHEK2):c.1153T>C(p.Cys385Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152238Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 251004Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135712
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461562Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727094
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152238Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74368
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:3
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This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 385 of the CHEK2 protein (p.Cys385Arg). This variant is present in population databases (rs587782817, gnomAD 0.004%). 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: 142917). 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 have shown that this missense change affects CHEK2 function (PMID: 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. -
not provided Uncertain:2
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a damaging effect: loss of CHEK2-mediated DNA damage response in yeast assays as well as impaired autophosphorylation and kinase activity in human cell-based assays (PMID: 30851065, 37449874); This variant is associated with the following publications: (PMID: 31398194, 32826389, 22419737, 19782031, 37449874, 30851065, 29522266) -
PM2, PS3_supporting -
Hereditary cancer-predisposing syndrome Uncertain:2
This missense variant replaces cysteine with arginine at codon 385 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373, 31398194). A functional study has demonstrated this variant to be damaging in a yeast based DNA damage response assay (PMID: 30851065). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/282412 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.C385R variant (also known as c.1153T>C), located in coding exon 10 of the CHEK2 gene, results from a T to C substitution at nucleotide position 1153. The cysteine at codon 385 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration behaved as non-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat. 2019 05;40:631-648). This alteration was reported as functionally impaired 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 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 specified Uncertain:1
Variant summary: CHEK2 c.1153T>C (p.Cys385Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251004 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1153T>C in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. At least two publications report experimental evidence evaluating an impact on protein function. The variant effect results in reducing normal activity (Delimitsou_2019, Stolarova_2023). The following publications have been ascertained in the context of this evaluation (PMID: 31398194, 30851065, 37449874). ClinVar contains an entry for this variant (Variation ID: 142917). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
CHEK2-related disorder Uncertain:1
The CHEK2 c.1153T>C variant is predicted to result in the amino acid substitution p.Cys385Arg. To our knowledge, this variant has not been reported in the literature in any patients affected with CHEK2-related conditions. It has, however, been reported as a damaging variant in a yeast-based functional assay (Delimitsou et al. 2019. PubMed I: 30851065). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-29091804-A-G). It is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142917/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at