Submissions for variant NM_007294.4(BRCA1):c.3004A>G (p.Asn1002Asp)

gnomAD frequency: 0.00001  dbSNP: rs786202665

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165586	SCV000216320	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-03	criteria provided, single submitter	clinical testing	The p.N1002D variant (also known as c.3004A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 3004. The asparagine at codon 1002 is replaced by aspartic acid, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 225000 alleles tested) in our clinical cohort. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be benign and deleterious by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.N1002D remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506213	SCV000600311	uncertain significance	not specified	2017-01-27	criteria provided, single submitter	clinical testing
Invitae	RCV000637571	SCV000759036	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 1002 of the BRCA1 protein (p.Asn1002Asp). This variant is present in population databases (rs786202665, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 186062). 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 with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000165586	SCV000909326	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-07	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000165586	SCV003849194	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).