Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000562978 | SCV000665198 | pathogenic | Hereditary cancer-predisposing syndrome | 2016-07-12 | criteria provided, single submitter | clinical testing | The p.L413* pathogenic mutation (also known as c.1238T>G), located in coding exon 10 of the CHEK2 gene, results from a T to G substitution at nucleotide position 1238. This changes the amino acid from a leucine to a stop codon within coding exon 10. Although this exact mutation has not been reported in the literature, another alteration resulting in the same termination codon (c.1238T>A) has been reported in 4/7051 female cases of breast cancer and not in 11241 matched controls in a Japanese cohort (Momozawa Y et al. Nat Commun, 2018 10;9:4083). In addition to the clinical data presented in the literature, 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. |
| Gene |
RCV000657757 | SCV000779509 | pathogenic | not provided | 2018-03-07 | criteria provided, single submitter | clinical testing | This variant is denoted CHEK2 c.1238T>G at the cDNA level and p.Leu413Ter (L413X) at the protein level. The substitution creates a nonsense variant, which changes a Leucine to a premature stop codon (TTA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic. |
| Labcorp Genetics |
RCV001865736 | SCV002173669 | pathogenic | Familial cancer of breast | 2023-05-10 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Leu413*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 481071). |
| Genetics and Molecular Pathology, |
RCV001865736 | SCV002761872 | likely pathogenic | Familial cancer of breast | 2021-03-19 | criteria provided, single submitter | clinical testing | |
| Myriad Genetics, |
RCV001865736 | SCV004043411 | pathogenic | Familial cancer of breast | 2023-06-28 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. |
| German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV004764791 | SCV005374636 | pathogenic | Hereditary breast ovarian cancer syndrome | 2024-08-13 | criteria provided, single submitter | curation | According to the ACMG SVI adaptation criteria we chose these criteria: PVS1 (very strong pathogenic): Truncating prior to c.1493; NMD expected, PM2 (supporting pathogenic): not in gnomAD V2, PM5 (supporting pathogenic): Truncating prior to c.1493; NMD expected |