ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.9224T>C (p.Ile3075Thr)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV004999106 SCV005625344 uncertain significance not provided 2024-11-08 criteria provided, single submitter clinical testing The BRCA2 c.9224T>C (p.Ile3075Thr) variant has been reported in the published literature in individuals affected with breast cancer (PMID: 33471991 (2021)) as well as reportedly healthy individuals (PMID: 30287823 (2018), 36243179 (2022)). This variant was also reported to be functionally neutral in a homologous recombination assay (PMID: 37731132 (2023)). The frequency of this variant in the general population, 0.0000066 (1/152220 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV005112514 SCV005815727 uncertain significance Hereditary breast ovarian cancer syndrome 2024-02-26 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 3075 of the BRCA2 protein (p.Ile3075Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). 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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