chr22-28696963-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PP3_Strong
The NM_007194.4(CHEK2):โc.1033C>Tโ(p.His345Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,460,156 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 (โ โ ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H345D) has been classified as Uncertain significance.
Frequency
Consequence
NM_007194.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHEK2 | NM_007194.4 | c.1033C>T | p.His345Tyr | missense_variant | 10/15 | ENST00000404276.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHEK2 | ENST00000404276.6 | c.1033C>T | p.His345Tyr | missense_variant | 10/15 | 1 | NM_007194.4 | P2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251194Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135780
GnomAD4 exome AF: 0.0000158 AC: 23AN: 1460156Hom.: 0 Cov.: 29 AF XY: 0.0000179 AC XY: 13AN XY: 726522
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 08, 2023 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2022 | This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 345 of the CHEK2 protein (p.His345Tyr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 220465). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 20, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 11, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 08, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 08, 2023 | The p.H345Y variant (also known as c.1033C>T), located in coding exon 9 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1033. The histidine at codon 345 is replaced by tyrosine, an amino acid with similar properties. This alteration has been reported in both breast and/or ovarian cancer cohort patients, as well as unaffected control individuals across studies (Decker B et al. J Med Genet, 2017 Nov;54:732-741; Dorling et al. N Engl J Med 2021 02;384:428-439; Hauke J et al. Cancer Med, 2018 Apr;7:1349-1358; Song H et al. J Med Genet, 2021 May;58:305-313). 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Li-Fraumeni syndrome 2 Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Department of Genetics, HCU Lozano Blesa | May 01, 2023 | Variant summary: CHEK2 c.1033C>T results in the replacement of His345 by a Tyr residue (p.His345Tyr). The variant was identified in 1 out of 396 patients analysed (freq: 0.0025, doi: 10.3389/fgene.2023.1274108). The patient was a woman that developed breast cancer at the age of 38 years (luminal-B tumor phenotype). One first-degree relative of her was also diagnosed with BC, although a co-segregation study could not be performed. His345 is located in the kinase domain, and is part of the well-conserved motif HRD (His345โArg-346โAsp347) in the catalytic loop of the protein. In this motif, His345 establishes an H-bond with the key catalytic residue Asp347. Thus, its replacement by a Tyr residue (bulkier) may detrimentally affect the catalytic activity of the protein. In addition, His345 forms a fair H-bond (~2.7 ร ) with the backbone of Asp368, located in the activation T-loop crucial for homodimerization. The variant is reported in gnomAD v4 in 23 cases out of 1460156 alleles analysed (freq=1.6x10-3 %). In ClinVar 8 reports appear classifying the variant as of Uncertain significance. Other replacements found at this position (H345Q, H345P, H345R, H345L, and H345D) are also classified by ClinVar as of Uncertain Significance. The metapredictor PirePred (relies on verdicts from other 15 predictor or metapredictor tools) and the AI-based predictor AlphaMissense classify His345Tyr as Pathogenic, whereas the ACMG classification tool Franklin suggests this variant as VUS (Uncertain Significance). Our in-silico study on the protein stability based on relaxation molecular dynamics simulations (doi: 10.3389/fgene.2023.1274108) indicates that His345Tyr induces conformational unstability on CHEK2 protein. Moreover, Stolarova L. et alโs functional study on KAP1 phosphorylation and CHEK2 autophosphorylation protein capability reports this variant as functionally impaired (PMID: 37449874). With all this information, we believe this variant have more chances of being Pathogenic. - |
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 15, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 26, 2019 | Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at