Submissions for variant NM_000059.4(BRCA2):c.5546G>A (p.Gly1849Asp)

gnomAD frequency: 0.00001  dbSNP: rs764527357

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001024258	SCV001186241	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-19	criteria provided, single submitter	clinical testing	The p.G1849D variant (also known as c.5546G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 5546. The glycine at codon 1849 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001055240	SCV001219619	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-05-05	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 825822). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is present in population databases (rs764527357, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1849 of the BRCA2 protein (p.Gly1849Asp).
Color Diagnostics, LLC DBA Color Health	RCV001024258	SCV001341633	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-21	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 1849 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 been identified in 2/248188 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.
Sema4, Sema4	RCV001024258	SCV002536145	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-22	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV001024258	SCV003848906	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).