Submissions for variant NM_007294.4(BRCA1):c.2500G>C (p.Gly834Arg)

gnomAD frequency: 0.00003  dbSNP: rs786202215

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164931	SCV000215620	likely benign	Hereditary cancer-predisposing syndrome	2019-11-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590464	SCV000698963	uncertain significance	not provided	2017-02-09	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.2500G>C (p.Gly834Arg) variant involves the alteration of a non-conserved nucleotide and is predicted to be benign by 3/4 in silico tools (SNPs&GO not captured due to low reliability index). The variant is located outside of some commonly known domains in BRCA1 protein (InterPro, UniPro). This variant is absent in 121354 control chromosomes from ExAC. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases, nor evaluated for functional impact by in vivo/vitro studies. A clinical diagnostic laboratory has reported this variant once in an individual undergoing BRCA1/2 testing without evidence to independently evaluate and has classified the variant as uncertain significance. Based on the currently available information, this variant is classified as a variant of uncertain significance (VUS).
Invitae	RCV000695556	SCV000824065	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 834 of the BRCA1 protein (p.Gly834Arg). This variant is present in population databases (rs786202215, gnomAD 0.006%). 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: 185491). 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	RCV000164931	SCV001340806	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-20	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 834 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). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_005660). This variant has been identified in 2/251008 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590464	SCV002046149	uncertain significance	not provided	2023-08-25	criteria provided, single submitter	clinical testing	In a large scale breast cancer association study, the variant was observed in an individual with breast cancer and not among unaffected control individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA1)). The frequency of this variant in the general population, 0.000008 (2/251008 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000164931	SCV003847623	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).