Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007194.4(CHEK2):c.276dupC(p.Trp93LeufsTer15) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P92P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
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]
CHEK2 Gene-Disease associations (from GenCC):
CHEK2-related cancer predisposition
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
Our verdict: Pathogenic. The variant received 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 22-28734445-A-AG is Pathogenic according to our data. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734445-A-AG is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 234677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Feb 24, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp93Leufs*15) 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). ClinVar contains an entry for this variant (Variation ID: 234677). For these reasons, this variant has been classified as Pathogenic. -
not providedPathogenic:1
Dec 08, 2015
GeneDx
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This duplication of one nucleotide in CHEK2 is denoted c.276dupC at the cDNA level and p.Trp93LeufsX15(W93LfsX15) at the protein level. The normal sequence, with the base that is duplicated in braces, is GCCCC{C}TGGG. The duplication causes a frameshift, which changes a Tryptophan to a Leucine at codon 93, and creates a premature stop codon at position 15 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Based on the currently available information, we consider this duplication to be a likely pathogenic variant. -
The c.276dupC pathogenic mutation, located in coding exon 1 of the CHEK2 gene, results from a duplication of C at nucleotide position 276, causing a translational frameshift with a predicted alternate stop codon (p.W93Lfs*15). 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. -