Submissions for variant NM_007294.4(BRCA1):c.3515A>G (p.Glu1172Gly)

gnomAD frequency: 0.00001  dbSNP: rs80357206

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130829	SCV000185726	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-06	criteria provided, single submitter	clinical testing	The p.E1172G variant (also known as c.3515A>G) is located in coding exon 9 of the BRCA1 gene. This alteration results from an A to G substitution at nucleotide position 3515. The glutamic acid at codon 1172 is replaced by glycine, an amino acid with similar properties. Two studies have predicted this alteration to be pathogenic using methods based on protein sequence conservation (Pavlicek A et al. Hum Mol Genet. 2004 Nov 15;13(22):2737-51; Burk-Herrick A et al. Mamm Genome. 2006 Mar;17(3):257-70). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985400	SCV001133554	uncertain significance	not provided	2024-04-16	criteria provided, single submitter	clinical testing	The BRCA1 c.3515A>G (p.Glu1172Gly) variant has been reported in the published literature to be located in a region of the BRCA1 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). To the best of our knowledge, this variant has not been reported in individuals with BRCA1-related disorders. The ancestral sequence method in the literature based on the mammalian protein alignment has predicted that this variant is deleterious (PMIDs: 16518693 (2006) and 15385441 (2004)). The frequency of this variant in the general population, 0.00013 (2/15428 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001322957	SCV001513854	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-07-10	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1172 of the BRCA1 protein (p.Glu1172Gly). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 54907). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130829	SCV003851834	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).
Myriad Genetics, Inc.	RCV000112108	SCV004186055	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112108	SCV000144780	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735475	SCV000863612	uncertain significance	Breast and/or ovarian cancer	2000-01-25	no assertion criteria provided	clinical testing