Submissions for variant NM_007294.4(BRCA1):c.886A>G (p.Arg296Gly)

gnomAD frequency: 0.00001  dbSNP: rs748675395

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000496938	SCV000586873	likely benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000574826	SCV000661082	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-05	criteria provided, single submitter	clinical testing	The p.R296G variant (also known as c.886A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 886. The arginine at codon 296 is replaced by glycine, an amino acid with dissimilar properties. This alteration was functional in a homology directed DNA repair (HDR) assay (Lu C et al. Nat Commun, 2015 Dec;6:10086). In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This variant was also reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is not 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.
Color Diagnostics, LLC DBA Color Health	RCV000574826	SCV000683374	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-19	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 296 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). One study suggested this variant may not impact homology-directed repair (PMID: 26689913). This variant has been reported in an individual affected with kidney renal clear cell carcinoma (PMID: 26689913). This variant has been identified in 1/246014 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.
Invitae	RCV000821194	SCV000961943	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-09-04	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. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 26689913). 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: 431183). This missense change has been observed in individual(s) with kidney renal cell carcinoma (PMID: 26689913). This variant is present in population databases (rs748675395, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 296 of the BRCA1 protein (p.Arg296Gly).
GeneDx	RCV001552518	SCV001773220	uncertain significance	not provided	2019-04-22	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21702907, 26689913)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001552518	SCV002774458	uncertain significance	not provided	2021-07-23	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000574826	SCV003847874	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).