Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_007194.4 | MANE Select | 1844 nt | 59–1690 |
| NM_007194.3 | Alternative | 1862 nt | 73–1704 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThe CHEK2 c.731A>G (p.Lys244Arg) variant has been reported in the published literature in individuals affected with breast cancer (PMID: 22114986 (2011), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared), 37449874 (2023)) as well as reportedly unaffected individuals (PMID: 22114986 (2011), 24728327 (2014)). Assessment of experimental evidence regarding the effect of this variant on protein function suggests it has no effect relevant to disease (PMID: 22114986 (2011), 37449874 (2023)). The frequency of this variant in the general population (Genome Aggregation Database, http://gnomad.broadinstitute.org) is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
This missense variant replaces lysine with arginine at codon 244 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function. A functional study has shown the mutant protein to exhibit kinase activity similar to the wild-type protein (PMID: 22114986). This variant has been reported in an individual affected with breast cancer (PMID: 22114986) and in two unaffected individuals (PMID: 22114986, 24728327). This variant has been identified in 3/282782 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 244 of the CHEK2 protein (p.Lys244Arg). This variant is present in population databases (rs587778193, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer, and an unaffected individual (PMID: 22114986). ClinVar contains an entry for this variant (Variation ID: 133889). 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 tolerated. Experimental studies have shown that this missense change does not substantially affect CHEK2 function (PMID: 22114986). 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.
"This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The CHEK2 K244R variant has been functionally characterized and exhibits kinase activity similar to the wild-type Chek2 in vitro. It also shows similar Kap1 phosphorylation and Chek2 autophosphorylation in CHEK2-null cells, indicating that this variant is predicted to have no effect on Chek2 protein function.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 47 bp |
| Donor Loss (DL) | 0.0 | -180 bp |
| Acceptor Gain (AG) | 0.0 | 169 bp |
| Donor Gain (DG) | 0.0 | -58 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, PVS1 is 'Null variant in a gene where loss of function is a known mechanism of disease'. The evidence for this variant shows it is a missense change (K244R), not a null variant. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to standard ACMG guidelines, PS1 is 'Same amino acid change as a known pathogenic variant regardless of nucleotide change'. The evidence for this variant shows no previously established pathogenic variant at residue K244. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, PS2 is 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. There is no information on de novo occurrence. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to standard ACMG guidelines, PS3 is 'Well-established functional studies supportive of a damaging effect on the gene or gene product'. The evidence shows functional studies demonstrate normal kinase activity, Kap1 phosphorylation, and autophosphorylation, indicating no damaging effect. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, PS4 is 'Prevalence in affected individuals significantly increased compared with controls'. There is no case-control or prevalence data. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, PM1 is 'Located in a mutational hot spot or well-established functional domain without benign variation'. There is no evidence that K244 lies in a mutational hotspot or critical domain. Therefore, this criterion is not applied.
PM2 (Moderate)
According to standard ACMG guidelines, PM2 is 'Absent from controls (or at extremely low frequency if recessive)'. The evidence shows a MAF of 0.00106% in gnomAD (3/282782 alleles), supporting extremely low frequency. Therefore, this criterion is applied at Moderate strength.
PM3 (Not Applied)
According to standard ACMG guidelines, PM3 is 'Detected in trans with a pathogenic variant for recessive disorders'. This variant is not evaluated in a recessive context and there is no data of it in trans with a pathogenic variant. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, PM4 is 'Protein length changes due to in-frame deletions/insertions or stop-loss variants'. This variant is a missense substitution without alteration of protein length. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, PM5 is 'Novel missense change at an amino acid residue where a different pathogenic missense change has been seen'. There are no known pathogenic missense variants at residue K244. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, PM6 is 'Assumed de novo, but without confirmation of paternity and maternity'. There is no data on de novo occurrence. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, PP1 is 'Co-segregation with disease in multiple affected family members'. There are no segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 is 'Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease'. CHEK2 pathogenic variants are predominantly truncating; missense is not a well-established common mechanism. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, PP3 is 'Multiple lines of computational evidence support a deleterious effect'. The computational evidence shows no predicted impact and SpliceAI score of 0. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, PP4 is 'Patient's phenotype or family history highly specific for a disease with a single genetic etiology'. No phenotype or family history data provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 is 'Reputable source reports variant as pathogenic without accessible evidence'. ClinVar reports this variant as VUS, not pathogenic. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, BA1 is 'Allele frequency is too high for the disorder'. The allele frequency is well below the threshold. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to standard ACMG guidelines, BS1 is 'Allele frequency is greater than expected for disorder'. The allele frequency (0.00106%) is not greater than expected for CHEK2-related disease. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, BS2 is 'Observed in healthy individuals for a dominant disorder with full penetrance'. There is no data on observation in healthy adult individuals. Therefore, this criterion is not applied.
BS3 (Strong)
According to standard ACMG guidelines, BS3 is 'Well-established functional studies show no damaging effect on protein function or splicing'. Functional studies demonstrate normal kinase activity, Kap1 phosphorylation, and autophosphorylation, indicating no damaging effect. Therefore, this criterion is applied at Strong strength.
BS4 (Not Applied)
According to standard ACMG guidelines, BS4 is 'Lack of segregation in affected family members'. No family segregation data are available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, BP1 is 'Missense variant in a gene where only LoF causes disease'. CHEK2 has disease-associated missense variants, so this does not apply. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 is 'Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant'. No such data are available. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 is 'In-frame indels in a repetitive region without known function'. This is a missense substitution, not an in-frame indel. Therefore, this criterion is not applied.
BP4 (Supporting)
According to standard ACMG guidelines, BP4 is 'Multiple lines of computational evidence suggest no impact on gene or gene product'. In silico predictions and SpliceAI (score 0) indicate no predicted impact. Therefore, this criterion is applied at Supporting strength.
BP5 (Not Applied)
According to standard ACMG guidelines, BP5 is 'Variant found in a case with an alternate molecular basis for disease'. No such case data are available. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, BP6 is 'Reputable source reports variant as benign without accessible evidence'. No reputable benign report exists. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, BP7 is 'Synonymous variant with no predicted impact on splicing'. This is a missense variant, not synonymous. Therefore, this criterion is not applied.