Submissions for variant NM_000059.4(BRCA2):c.6715G>C (p.Glu2239Gln)

dbSNP: rs276174876

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000573449	SCV000668775	uncertain significance	Hereditary cancer-predisposing syndrome	2017-03-14	criteria provided, single submitter	clinical testing	The p.E2239Q variant (also known as c.6715G>C), located in coding exon 10 of the BRCA2 gene, results from a G to C substitution at nucleotide position 6715. The glutamic acid at codon 2239 is replaced by glutamine, 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000573449	SCV001359388	uncertain significance	Hereditary cancer-predisposing syndrome	2019-11-25	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 2239 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000573449	SCV003847395	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).
Labcorp Genetics (formerly Invitae), Labcorp	RCV003645049	SCV004504474	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-03-09	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 483090). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 2239 of the BRCA2 protein (p.Glu2239Gln). 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. 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.