Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001062326 | SCV001227120 | uncertain significance | Familial cancer of breast | 2024-01-10 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 107 of the CHEK2 protein (p.Glu107Lys). This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. This variant is present in population databases (rs775320614, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 30303537). ClinVar contains an entry for this variant (Variation ID: 856789). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |
| Ambry Genetics | RCV002320320 | SCV002609127 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-09-11 | criteria provided, single submitter | clinical testing | The c.319G>A variant (also known as p.E107K), located in coding exon 1 of the CHEK2 gene, results from a G to A substitution at nucleotide position 319. The amino acid change results in glutamic acid to lysine at codon 107, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 1, which makes it likely to have some effect on normal mRNA splicing. This alteration was identified in 1/1207 cases of French women diagnosed with breast cancer who had a sister with breast cancer and were BRCA1 and BRCA2 negative and 0/1199 general population controls (Girard E et al. Int J Cancer, 2019 04;144:1962-1974). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. In addition, as a missense substitution, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |