Submissions for variant NM_000059.4(BRCA2):c.5084A>T (p.Glu1695Val)

dbSNP: rs397507347

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480557	SCV000566661	uncertain significance	not provided	2015-05-20	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.5084A>T at the cDNA level, p.Glu1695Val (E1695V) at the protein level, and results in the change of a Glutamic Acid to a Valine (GAA>GTA). Using alternate nomenclature, this variant would be defined as BRCA2 5312A>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Glu1695Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glutamic Acid and Valine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Glu1695Val occurs at a position that is not conserved and is located in the BRC repeat region (Narod 2004, Roy 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Glu1695Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000569626	SCV000665966	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-01	criteria provided, single submitter	clinical testing	The p.E1695V variant (also known as c.5084A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 5084. The glutamic acid at codon 1695 is replaced by valine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000569626	SCV001349516	uncertain significance	Hereditary cancer-predisposing syndrome	2020-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with valine at codon 1695 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. An experimental functional study reported this variant as neutral using PARP-sensitivity, BRCA2 rescue assays (DOI: 10.1101/2020.01.17.911057). This variant has not been reported in individuals affected with hereditary cancer in the literature. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002525787	SCV002992281	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-04-15	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 1695 of the BRCA2 protein (p.Glu1695Val). This variant is not present in population databases (gnomAD no frequency). 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: 419093). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000569626	SCV003846981	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).