chr22-28699873-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_007194.4(CHEK2):c.973A>G(p.Lys325Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000752 in 1,461,826 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K325M) 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 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHEK2 | NM_007194.4 | c.973A>G | p.Lys325Glu | missense_variant | 9/15 | ENST00000404276.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHEK2 | ENST00000404276.6 | c.973A>G | p.Lys325Glu | missense_variant | 9/15 | 1 | NM_007194.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 0AN: 152158Hom.: 0 Cov.: 31 FAILED QC
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461826Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6AN XY: 727206
GnomAD4 genome ? Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 152158Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74324
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 03, 2023 | The p.K325E variant (also known as c.973A>G), located in coding exon 8 of the CHEK2 gene, results from an A to G substitution at nucleotide position 973. The lysine at codon 325 is replaced by glutamic acid, an amino acid with similar properties. 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 17, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 24, 2023 | This missense variant replaces lysine with glutamic acid at codon 325 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). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 2/53461 controls (PMID: 33471991). This variant has not been identified 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 provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 20, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2017 | - - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 325 of the CHEK2 protein (p.Lys325Glu). This variant is not present in population databases (gnomAD no frequency). 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: 420222). 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