Submissions for variant NM_000059.4(BRCA2):c.9501G>C (p.Glu3167Asp)

gnomAD frequency: 0.00001  dbSNP: rs80359808

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000216268	SCV000279979	uncertain significance	not provided	2016-03-10	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.9501G>C at the cDNA level, p.Glu3167Asp (E3167D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAG>GAC). Using alternate nomenclature, this variant would be defined as BRCA2 9729G>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Glu3167Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic Acid and Aspartic Acid share similar properties, this is considered a conservative amino acid substitution. BRCA2 Glu3167Asp occurs at a position that is not conserved and is not located in a known functional domain (Cole 2011). While protein-based in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function, multiple splicing models predict that this variant may damage the nearby natural splice donor site. Based on currently available evidence, it is unclear whether BRCA2 Glu3167Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000216268	SCV000296552	uncertain significance	not provided	2020-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000582949	SCV000689203	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-14	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 3167 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). To our knowledge, functional studies have not been reported for this variant. 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	RCV002516209	SCV003299952	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-04-01	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 3167 of the BRCA2 protein (p.Glu3167Asp). This variant also falls at the last nucleotide of exon 25, which is part of the consensus splice site for this exon. 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: 234895). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Ambry Genetics	RCV000582949	SCV005032066	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-23	criteria provided, single submitter	clinical testing	The c.9501G>C variant (also known as p.E3167D), located in coding exon 24 of the BRCA2 gene, results from a G to C substitution at nucleotide position 9501. The amino acid change results in glutamic acid to aspartic acid at codon 3167, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. However, this change occurs in the last base pair of coding exon 24, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Direct RNA evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.