chr22-28696969-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_007194.4(CHEK2):āc.1027A>Gā(p.Ile343Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,611,390 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I343S) 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 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHEK2 | NM_007194.4 | c.1027A>G | p.Ile343Val | missense_variant | 10/15 | ENST00000404276.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHEK2 | ENST00000404276.6 | c.1027A>G | p.Ile343Val | missense_variant | 10/15 | 1 | NM_007194.4 | P2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251194Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135782
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1459208Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1AN XY: 726030
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74336
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 27, 2023 | This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 343 of the CHEK2 protein (p.Ile343Val). ClinVar contains an entry for this variant (Variation ID: 530054). 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. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 02, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 27, 2024 | The p.I343V variant (also known as c.1027A>G), located in coding exon 9 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1027. The isoleucine at codon 343 is replaced by valine, an amino acid with highly similar properties. This alteration was 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 amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at