ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.2221G>A (p.Val741Ile)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002428087 SCV002730199 uncertain significance Hereditary cancer-predisposing syndrome 2022-10-18 criteria provided, single submitter clinical testing The p.V741I variant (also known as c.2221G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 2221. The valine at codon 741 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is not 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV002428087 SCV003846588 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).
All of Us Research Program, National Institutes of Health RCV004007408 SCV004835368 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2023-11-30 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV005098016 SCV005812920 uncertain significance Hereditary breast ovarian cancer syndrome 2024-07-02 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 741 of the BRCA2 protein (p.Val741Ile). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with a personal or family history of cancer (PMID: 29310832). ClinVar contains an entry for this variant (Variation ID: 1787940). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.

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