rs587780173
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007194.4(CHEK2):c.1254del(p.Phe418LeufsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
CHEK2
NM_007194.4 frameshift
NM_007194.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.406
Genes affected
CHEK2 (HGNC:16627): (checkpoint kinase 2) In response to DNA damage and replication blocks, cell cycle progression is halted through the control of critical cell cycle regulators. The protein encoded by this gene is a cell cycle checkpoint regulator and putative tumor suppressor. It contains a forkhead-associated protein interaction domain essential for activation in response to DNA damage and is rapidly phosphorylated in response to replication blocks and DNA damage. When activated, the encoded protein is known to inhibit CDC25C phosphatase, preventing entry into mitosis, and has been shown to stabilize the tumor suppressor protein p53, leading to cell cycle arrest in G1. In addition, this protein interacts with and phosphorylates BRCA1, allowing BRCA1 to restore survival after DNA damage. Mutations in this gene have been linked with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53. Also, mutations in this gene are thought to confer a predisposition to sarcomas, breast cancer, and brain tumors. This nuclear protein is a member of the CDS1 subfamily of serine/threonine protein kinases. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 22-28695714-TA-T is Pathogenic according to our data. Variant chr22-28695714-TA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 128052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHEK2 | NM_007194.4 | c.1254del | p.Phe418LeufsTer19 | frameshift_variant | 11/15 | ENST00000404276.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHEK2 | ENST00000404276.6 | c.1254del | p.Phe418LeufsTer19 | frameshift_variant | 11/15 | 1 | NM_007194.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial cancer of breast Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 29, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 128052). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 26681312, 29520813). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe418Leufs*19) 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jun 28, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 29, 2016 | This pathogenic variant is denoted CHEK2 c.1254delT at the cDNA level and p.Phe418LeufsX19 (F418LfsX19) at the protein level. The normal sequence, with the base that is deleted in braces, is CTTTT[T]ATCT. The deletion causes a frameshift, which changes a Phenylalanine to a Leucine at codon 418, and creates a premature stop codon at position 19 of the new reading frame. This variant was observed in at least one individual with breast cancer (Susswein 2015), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be likely pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 27, 2019 | The c.1254delT pathogenic mutation, located in coding exon 10 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 1254, causing a translational frameshift with a predicted alternate stop codon (p.F418Lfs*19). This alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel in a patient with breast cancer (Susswein LR et al. Genet. Med., 2016 08;18:823-32). This alteration has also been reported in two individuals with prostate cancer (Wu Y et al. Prostate, 2018 06;78:607-615). 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
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at