Submissions for variant NM_000059.4(BRCA2):c.5377A>C (p.Asn1793His)

dbSNP: rs1593905298

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001023994	SCV001185944	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-26	criteria provided, single submitter	clinical testing	The p.N1793H variant (also known as c.5377A>C), located in coding exon 10 of the BRCA2 gene, results from an A to C substitution at nucleotide position 5377. The asparagine at codon 1793 is replaced by histidine, an amino acid with similar properties. This amino acid position is poorly conserved in available 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001222464	SCV001394563	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-12-15	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: 825683). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 1793 of the BRCA2 protein (p.Asn1793His).
Color Diagnostics, LLC DBA Color Health	RCV001023994	SCV001735704	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-22	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with histidine at codon 1793 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). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001023994	SCV003847200	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).
All of Us Research Program, National Institutes of Health	RCV004004644	SCV004846566	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with histidine at codon 1793 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). 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.