Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000130206 | SCV000185044 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-06-29 | criteria provided, single submitter | clinical testing | The p.P128L variant (also known as c.383C>T), located in coding exon 2 of the CHEK2 gene, results from a C to T substitution at nucleotide position 383. The proline at codon 128 is replaced by leucine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, 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. |
Invitae | RCV000227657 | SCV000289684 | uncertain significance | Familial cancer of breast | 2024-01-03 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 128 of the CHEK2 protein (p.Pro128Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 141613). 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. 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. |
Color Diagnostics, |
RCV000130206 | SCV000684634 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-08-31 | criteria provided, single submitter | clinical testing | This missense variant replaces proline with leucine at codon 128 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown this variant protein does not impact protein localization or kinase activity (PMID: 37449874). In a large breast cancer case-control meta analysis conducted by the ENIGMA consortium, this variant was reported in 3/73048 cases and 1/88658 unaffected controls (PMID: 37449874). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |