22-28734663-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_007194.4(CHEK2):c.59A>G(p.Gln20Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q20H) has been classified 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 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHEK2 | NM_007194.4 | c.59A>G | p.Gln20Arg | missense_variant | 2/15 | ENST00000404276.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHEK2 | ENST00000404276.6 | c.59A>G | p.Gln20Arg | missense_variant | 2/15 | 1 | NM_007194.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151926Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000808 AC: 2AN: 247598Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 134102
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461764Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727182
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151926Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74198
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 26, 2020 | Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Absent from breast cancer cases but observed in control populations (Momozawa 2018); This variant is associated with the following publications: (PMID: 30287823) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 23, 2018 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 05, 2024 | The p.Q20R variant (also known as c.59A>G), located in coding exon 1 of the CHEK2 gene, results from an A to G substitution at nucleotide position 59. The glutamine at codon 20 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 10, 2021 | This missense variant replaces glutamine with arginine at codon 20 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/247598 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 19, 2017 | Variant summary: The c.59A>G (p.Gln20Arg) in CHEK2 gene is a missense variant involves a non-conserved nucleotide and 2/4 in silico tools predict benign outcome, however no functional studies supporting these predictions were published at the time of evaluation. The variant is located within the SQ/TQ cluster domain, although the functional impact of this change on protein remains unclear. The c.7984A>G is present in the control population datasets of ExAC and gnomAD at a low frequency of 0.000008 (2/ 242298 chrs tested), which does not exceed the maximum expected allele frequency for a pathogenic variant of 0.000028. To our knowledge, the variant has not been reported in affected individuals via published reports, but is cited as VUS by reputable databases/clinical laboratories. Taken together, the variant was classified as VUS, until new information becomes available. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 20 of the CHEK2 protein (p.Gln20Arg). This variant is present in population databases (rs753257724, gnomAD 0.002%). 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: 232706). 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. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at