Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000561232 | SCV000661732 | pathogenic | Hereditary cancer-predisposing syndrome | 2017-12-22 | criteria provided, single submitter | clinical testing | The c.1238_1246delTAGGAGTTAinsAGGAG pathogenic mutation (also known as p.L413*), located in coding exon 10 of the CHEK2 gene, results from the deletion of 9 nucleotides and insertion of 5 nucleotides at positions 1238 to 1246. This changes the amino acid from a leucine to a stop codon within coding exon 10. 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. |
| Labcorp Genetics |
RCV003470813 | SCV000757145 | pathogenic | Familial cancer of breast | 2021-09-09 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 479553). 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 31206626). For these reasons, this variant has been classified as Pathogenic. |
| Color Diagnostics, |
RCV000561232 | SCV001346452 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-06-23 | criteria provided, single submitter | clinical testing | This variant creates a premature termination codon in exon 11 of the CHEK2 gene. The variant protein is also known as p.Leu413_Ile416delinsTer. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003230544 | SCV003928337 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2023-04-24 | criteria provided, single submitter | clinical testing | Variant summary: CHEK2 c.1238_1246delinsAGGAG (p.Leu413X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Two missense variants resulting in the same termination codon are classified as pathogenic/likely pathogenic in ClinVar and have been observed in individuals with cancer (HGMD). Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250208 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1238_1246delinsAGGAG in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Baylor Genetics | RCV003470813 | SCV004217501 | pathogenic | Familial cancer of breast | 2023-10-16 | criteria provided, single submitter | clinical testing |