ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.2111C>T (p.Pro704Leu)

gnomAD frequency: 0.00001  dbSNP: rs768323836
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000637734 SCV000759207 uncertain significance Hereditary breast ovarian cancer syndrome 2024-09-20 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 704 of the BRCA2 protein (p.Pro704Leu). This variant is present in population databases (rs768323836, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 531404). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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 RCV002420715 SCV002726991 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-24 criteria provided, single submitter clinical testing The p.P704L variant (also known as c.2111C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 2111. The proline at codon 704 is replaced by leucine, an amino acid with similar properties. This amino acid position is poorly 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV002420715 SCV003846504 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).

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