Submissions for variant NM_007294.4(BRCA1):c.900A>C (p.Glu300Asp)

dbSNP: rs80356861

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000049182	SCV000077195	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-04-08	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 55747). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is present in population databases (rs80356861, gnomAD 0.0009%). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 300 of the BRCA1 protein (p.Glu300Asp). 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. 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.
GeneDx	RCV000236740	SCV000293329	uncertain significance	not provided	2019-11-22	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek 2016); Also known as 1019A>C; This variant is associated with the following publications: (PMID: 12531920, 15385441, 16518693)
Color Diagnostics, LLC DBA Color Health	RCV000771560	SCV000904137	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 300 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 33888336). This variant has been identified in 1/251302 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.
Ambry Genetics	RCV000771560	SCV001179891	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-24	criteria provided, single submitter	clinical testing	The p.E300D variant (also known as c.900A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide position 900. The glutamic acid at codon 300 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000771560	SCV003846307	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	RCV000111506	SCV004818396	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 300 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 33888336). This variant has been identified in 1/251302 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.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111506	SCV000143948	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing