Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2BP4_StrongBP6_Very_StrongBP7
The NM_007194.4(CHEK2):c.1284T>G(p.Ser428Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S428S) has been classified as Likely benign.
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: Benign. The variant received -11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.52).
BP6
Variant 22-28695218-A-C is Benign according to our data. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28695218-A-C is described in CliVar as Benign/Likely_benign. Clinvar id is 818798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=1.65 with no splicing effect.
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Familial cancer of breastBenign:1
Oct 07, 2024
Myriad Genetics, Inc.
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -