Submissions for variant NM_007294.4(BRCA1):c.2723A>C (p.Glu908Ala)

dbSNP: rs1064794969

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000582231	SCV000688398	uncertain significance	Hereditary cancer-predisposing syndrome	2020-02-03	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with alanine at codon 908 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284393	SCV001470166	uncertain significance	not provided	2020-03-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002529215	SCV003207550	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-06-08	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 BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 491052). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 908 of the BRCA1 protein (p.Glu908Ala).
University of Washington Department of Laboratory Medicine, University of Washington	RCV000582231	SCV003849404	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).
Ambry Genetics	RCV000582231	SCV005025831	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-01	criteria provided, single submitter	clinical testing	The p.E908A variant (also known as c.2723A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide position 2723. The glutamic acid at codon 908 is replaced by alanine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.