BRCA2 NM_000059.4:c.4516T>C, Phe1506Leu

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1506 of the BRCA2 protein (p.Phe1506Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 34178674). ClinVar contains an entry for this variant (Variation ID: 231190). 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.

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).

This missense variant replaces phenylalanine with leucine at codon 1506 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant has been reported to be functional in a haploidized cell proliferation assay (PMID: 35190686). This variant has been reported in an individual affected with breast cancer (PMID: 34178674). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

The BRCA2 c.4516T>C (p.Phe1506Leu) variant has been reported in the published literature in an individual with breast cancer (PMID: 34178674 (2021)), and described to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). A functional study demonstrated that this variant had an inconclusive effect on protein function, being reported as functional in a saturation prime editing (SPE) assay in haploidized cell model (PMID: 35190686 (2022)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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.