Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000165518 | SCV000216250 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-07-26 | criteria provided, single submitter | clinical testing | The p.L2604P pathogenic mutation (also known as c.7811T>C), located in coding exon 16 of the BRCA2 gene, results from a T to C substitution at nucleotide position 7811. The leucine at codon 2604 is replaced by proline, an amino acid with similar properties. This variant was non-functional in a homology-directed DNA repair (HDR) assay (Richardson ME et al. Am J Hum Genet, 2021 Mar;108:458-468). In addition, in multiple other assays testing BRCA2 function, this variant showed functionally abnormal results (Ikegami M et al. Nat Commun, 2020 May;11:2573; Hu C et al. Am J Hum Genet, 2024 Mar;111:584-593). Based on internal structural assessment, this alteration is expected to destabilize the HD domain, in which other pathogenic alterations are present (Yang H et al. Science, 2002 Sep;297:1837-48). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. |
| Gene |
RCV000755223 | SCV000321484 | uncertain significance | not provided | 2020-10-20 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29752822, 29805665, 32444794) |
| ARUP Laboratories, |
RCV000755223 | SCV000602847 | uncertain significance | not provided | 2017-08-03 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV003644903 | SCV004538901 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2024-12-28 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 2604 of the BRCA2 protein (p.Leu2604Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal or family history of breast and/or ovarian cancer (PMID: 29752822). ClinVar contains an entry for this variant (Variation ID: 96859). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 35736817). 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. |
| Sharing Clinical Reports Project |
RCV000082980 | SCV000115054 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 2 | 2013-03-11 | no assertion criteria provided | clinical testing |