Submissions for variant NM_000059.4(BRCA2):c.8591C>T (p.Ala2864Val)

dbSNP: rs80359116

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165226	SCV000215940	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-13	criteria provided, single submitter	clinical testing	The p.A2864V variant (also known as c.8591C>T), located in coding exon 19 of the BRCA2 gene, results from a C to T substitution at nucleotide position 8591. The alanine at codon 2864 is replaced by valine, an amino acid with similar properties. Using a computational method that produces a probabilistic likelihood ratio predictive of whether a missense variant impairs protein function, this alteration is predicted to be neutral (Karchin R et al. Cancer Inform, 2008 Apr;6:203-16). This amino acid position is not well conserved in available vertebrate species, and valine is the reference amino acid in other 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003476934	SCV000600816	uncertain significance	not provided	2023-06-04	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in healthy individuals during a large breast cancer association study (PMID: 33471991 (2021)). 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.
Color Diagnostics, LLC DBA Color Health	RCV000165226	SCV000906509	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001352290	SCV001546834	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2864 of the BRCA2 protein (p.Ala2864Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 52629). 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.
Baylor Genetics	RCV003460621	SCV004213702	uncertain significance	Familial cancer of breast	2023-08-05	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113966	SCV000147410	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732634	SCV005364735	uncertain significance	BRCA2-related disorder	2024-06-09	no assertion criteria provided	clinical testing	The BRCA2 c.8591C>T variant is predicted to result in the amino acid substitution p.Ala2864Val. This variant has been reported in the literature in an individual with breast cancer and in healthy individuals (Szabo C et al 2000. PubMed ID: 10923033; Breast Cancer Association Consortium et al 2021. PubMed ID: 33471991). This variant is absent in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as a variant of uncertain significance by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/52629/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.