Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000576138 | SCV000666385 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-09-24 | criteria provided, single submitter | clinical testing | The c.592G>C variant (also known as p.V198L), located in coding exon 3 of the CHEK2 gene, results from a G to C substitution at nucleotide position 592. The amino acid change results in valine to leucine at codon 198, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 3, which makes it likely to have some effect on normal mRNA splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Another alteration impacting the same donor site (c.592+1G>A) has been shown to have a similar impact on splicing (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Invitae | RCV000686285 | SCV000813797 | uncertain significance | Familial cancer of breast | 2023-03-16 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown this missense change is associated with multiple alternative transcripts involving intronic insertion, but one or more of the resulting mRNA isoform(s) may be naturally occurring (Invitae). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 481730). 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 replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 198 of the CHEK2 protein (p.Val198Leu). This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. |
| Sema4, |
RCV000576138 | SCV002537622 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-12-29 | criteria provided, single submitter | curation | |
| Prevention |
RCV003392407 | SCV004119054 | uncertain significance | CHEK2-related condition | 2023-10-04 | criteria provided, single submitter | clinical testing | The CHEK2 c.592G>C variant is predicted to result in the amino acid substitution p.Val198Leu. This variant is located at the last nucleotide of the exon and is predicted to abolish the canonical splice donor site (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant has conflicting interpretations of uncertain and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/481730/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |