22-28734649-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_007194.4(CHEK2):c.73G>A(p.Val25Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_007194.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CHEK2 | NM_007194.4 | c.73G>A | p.Val25Ile | missense_variant | 2/15 | ENST00000404276.6 | NP_009125.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CHEK2 | ENST00000404276.6 | c.73G>A | p.Val25Ile | missense_variant | 2/15 | 1 | NM_007194.4 | ENSP00000385747 | P2 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151896Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 248530Hom.: 0 AF XY: 0.00000744 AC XY: 1AN XY: 134488
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461816Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7AN XY: 727204
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152012Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74276
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 27, 2023 | This missense variant replaces valine with isoleucine at codon 25 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). In complementation assays in human CHEK2-knockout cells, this variant did not impact CHK2 autophosphorylation or KAP1 phosphorylation (PMID: 37449874). This variant has been reported in individuals affected with breast cancer (PMID: 37373225) and pancreatic cancer (PMID: 32255556). This variant has been reported in two breast cancer case-control meta analyses; in 2/73048 cases and 1/88658 controls (PMID: 37449874) and 2/60466 cases and 3/53461 unaffected controls (PMID: 33471991;Leiden Open Variation Database DB-ID CHEK2_000595). This variant has been identified in 3/248530 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 23, 2022 | The p.V25I variant (also known as c.73G>A), located in coding exon 1 of the CHEK2 gene, results from a G to A substitution at nucleotide position 73. The valine at codon 25 is replaced by isoleucine, an amino acid with highly similar properties. This variant was identified in 1/177 individuals with pancreatic ductal adenocarcinoma undergoing multi-gene panel testing (Cremin C et al. Cancer Med, 2020 06;9:4004-4013). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 01, 2023 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 25 of the CHEK2 protein (p.Val25Ile). This variant is present in population databases (rs142243299, gnomAD 0.007%). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 32255556). ClinVar contains an entry for this variant (Variation ID: 140965). 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. 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