rs587781519
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PVS1_Moderate
The NM_007194.4(CHEK2):βc.1596delβ(p.Thr533GlnfsTer33) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000877 in 1,596,312 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ). Synonymous variant affecting the same amino acid position (i.e. T532T) has been classified as Likely benign.
Frequency
Consequence
NM_007194.4 frameshift
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.1596del | p.Thr533GlnfsTer33 | frameshift_variant | 15/15 | ENST00000404276.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHEK2 | ENST00000404276.6 | c.1596del | p.Thr533GlnfsTer33 | frameshift_variant | 15/15 | 1 | NM_007194.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152202Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000856 AC: 2AN: 233692Hom.: 0 AF XY: 0.00000779 AC XY: 1AN XY: 128342
GnomAD4 exome AF: 0.00000831 AC: 12AN: 1444110Hom.: 0 Cov.: 30 AF XY: 0.00000835 AC XY: 6AN XY: 718796
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74348
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 20, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Aug 27, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 17, 2023 | 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 141133). This frameshift has been observed in individual(s) with breast cancer (PMID: 30303537). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change results in a frameshift in the CHEK2 gene (p.Thr533Glnfs*33). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 11 amino acid(s) of the CHEK2 protein and extend the protein by 21 additional amino acid residues. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 02, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation as the last 11 amino acids are replaced with 32 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; Observed in individuals with breast cancer (Girard 2019); This variant is associated with the following publications: (PMID: 29615459, 30303537) - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 21, 2023 | The c.1596delC variant, located in coding exon 14 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 1596, causing a translational frameshift with a predicted alternate stop codon (p.T533Qfs*33). This alteration was identified in 2/1207 cases of French women diagnosed with breast cancer who had a sister with breast cancer and were BRCA1 and BRCA2 negative and 0/1199 general population controls (Girard E et al. Int J Cancer, 2019 04;144:1962-1974). This deletion and subsequent frameshift occur near the 3' terminus of CHEK2 and result in removal of the last 11 amino acids of CHK2 and insertion of 32 amino acids to the C-terminus, resulting in the elongation of the protein by 21 amino acids. The exact functional impact of these inserted amino acids is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 03, 2022 | This variant deletes 1 nucleotide in exon 15 of the CHEK2 gene, creating a frameshift at codon 533, replacing the last 11 amino acids and extends the length of the encoded protein by 21 amino acids. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with familial breast cancer who lack pathogenic variants in the BRCA1 or BRCA2 gene (PMID: 30303537) and in an individual with early-onset breast cancer (Color data). This variant has been identified in 3/265102 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at