Submissions for variant NM_007294.4(BRCA1):c.2620A>G (p.Asn874Asp)

dbSNP: rs1064795862

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001016127	SCV001177044	uncertain significance	Hereditary cancer-predisposing syndrome	2018-11-28	criteria provided, single submitter	clinical testing	The p.N874D variant (also known as c.2620A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 2620. The asparagine at codon 874 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create a new alternate splice acceptor site; however, direct evidence is unavailable. 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	RCV001860817	SCV002153375	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-10-15	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 821584). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with aspartic acid at codon 874 of the BRCA1 protein (p.Asn874Asp). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and aspartic acid.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001016127	SCV003851030	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).