Submissions for variant NM_000059.4(BRCA2):c.8060T>C (p.Val2687Ala)

gnomAD frequency: 0.00001  dbSNP: rs374625452

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213166	SCV000273472	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-22	criteria provided, single submitter	clinical testing	The p.V2687A variant (also known as c.8060T>C), located in coding exon 17 of the BRCA2 gene, results from a T to C substitution at nucleotide position 8060. The valine at codon 2687 is replaced by alanine, an amino acid with similar properties. This variant was similar to wildtype in a homology-directed DNA repair (HDR) assay (Ambry internal data). However, based on in silico and modeling tools, this alteration is expected to be worse than other likely pathogenic substitutions at this same amino acid (Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000213166	SCV002051849	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-14	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 2687 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 32068069). This variant has been identified in 2/251248 chromosomes 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853511	SCV002222333	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 2687 of the BRCA2 protein (p.Val2687Ala). This variant is present in population databases (rs374625452, gnomAD 0.007%). 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: 230057). 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. 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.