ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.10040T>C (p.Ile3347Thr)

gnomAD frequency: 0.00001  dbSNP: rs587782373
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131359 SCV000186335 uncertain significance Hereditary cancer-predisposing syndrome 2022-05-04 criteria provided, single submitter clinical testing The p.I3347T variant (also known as c.10040T>C), located in coding exon 26 of the BRCA2 gene, results from a T to C substitution at nucleotide position 10040. The isoleucine at codon 3347 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in one patient with early-onset breast cancer from a cohort of 132 Italian breast and/or ovarian cancer patients (Concolino P et al. Int J Mol Sci, 2019 Jul;20:). 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000816199 SCV000956696 uncertain significance Hereditary breast ovarian cancer syndrome 2024-07-30 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 3347 of the BRCA2 protein (p.Ile3347Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 31336956, 32438681). ClinVar contains an entry for this variant (Variation ID: 142308). 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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