chr22-28724990-TAG-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007194.4(CHEK2):βc.577_578delβ(p.Leu193LysfsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. L193L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_007194.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHEK2 | NM_007194.4 | c.577_578del | p.Leu193LysfsTer4 | frameshift_variant | 4/15 | ENST00000404276.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHEK2 | ENST00000404276.6 | c.577_578del | p.Leu193LysfsTer4 | frameshift_variant | 4/15 | 1 | NM_007194.4 | P2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251408Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135894
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461818Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 727210
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | This sequence change creates a premature translational stop signal (p.Leu193Lysfs*4) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant is present in population databases (rs775167943, gnomAD 0.006%). 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: 460844). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jun 26, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 24, 2021 | The c.577_578delCT pathogenic mutation, located in coding exon 3 of the CHEK2 gene, results from a deletion of two nucleotides at nucleotide positions 577 to 578, causing a translational frameshift with a predicted alternate stop codon (p.L193Kfs*4). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at