Submissions for variant NM_007294.4(BRCA1):c.1396C>G (p.Arg466Gly)

dbSNP: rs80356964

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000111607	SCV000488369	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-03-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000509950	SCV000607876	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-17	criteria provided, single submitter	clinical testing	The p.R466G variant (also known as c.1396C>G), located in coding exon 9 of the BRCA1 gene, results from a C to G substitution at nucleotide position 1396. The arginine at codon 466 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been identified in Moroccan and Saudi Arabian high-risk breast cancer cohorts (Tazzite A et al. Gynecol. Oncol. 2012 Jun;125:687-92; Abulkhair O et al. J Glob Oncol, 2018 08;4:1-9). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000509950	SCV000682957	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 466 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 reported in two individuals affected with breast or ovarian cancer (PMID: 22425665, 30199306) and in a multifactorial analysis with likelihood ratios for pathogenicity based on co-occurrence with a pathogenic covariant and family history of 1.0673 and 0.9148, respectively (PMID: 31131967). This variant also has been reported in an individual affected with ovarian cancer that exhibited microsatellite instability and loss of MSH6 and the presence of a BRCA1 truncation variant in the last coding exon (PMID: 32885271). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586875	SCV000698858	uncertain significance	not provided	2017-03-07	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.1396C>G (p.Arg466Gly) variant located in the serine-rich domain (via InterPro) involves the alteration of a non-conserved nucleotide, which 4/5 in silico tools predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was absent in 121376 control chromosomes (ExAC). A publication cites the variant in an affected individual with limited information (ie, no cosegregation information). In addition, multiple clinical diagnostic laboratories classified this variant as uncertain significance. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586875	SCV000887622	uncertain significance	not provided	2023-01-17	criteria provided, single submitter	clinical testing	It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 30199306 (2018), 22425665 (2012)). 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.
Invitae	RCV001339849	SCV001533624	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 466 of the BRCA1 protein (p.Arg466Gly). This variant is not present in population databases (gnomAD no frequency). 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: 54240). 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.
GeneDx	RCV000586875	SCV001818128	uncertain significance	not provided	2023-07-07	criteria provided, single submitter	clinical testing	Observed in individuals with a personal and/or family history of breast and/or ovarian cancer, in one patient co-occurring with a BRCA1 pathogenic variant (Tazzite et al., 2012; Abulkhair et al., 2018; Lerner-Ellis et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 1515C>G; This variant is associated with the following publications: (PMID: 16518693, 31131967, 12531920, 22425665, 30199306, 15343273, 29884841, 32377563, 31911673, 32885271)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000509950	SCV003851325	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).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492376	SCV004240227	uncertain significance	Breast and/or ovarian cancer	2023-01-18	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111607	SCV000144082	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000111607	SCV001552566	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing	The BRCA1 p.Arg466Gly variant was identified in 1 of 80 proband chromosomes (frequency: 0.01) from Moroccan individuals or families with early onset and familial breast/ovarian cancer (Tazzite_2012_22425665). Results of two evolutionary models predicting the significance of specific sites in BRCA1 exon 11 were conflicting, 1 study finding the variant had a functional effect and the other finding it did not have a functional effect (Burk-Herrick_2005_16518693, Fleming_2003_12531920). The variant was also identified in dbSNP (ID: rs80356964) “With Uncertain significance,other allele”, ClinVar (classified uncertain significance by Counsyl, Ambry Genetics and BIC; and classification not provided by Invitae), Clinvitae (1x), LOVD 3.0 (1x), and BIC Database (1x, with unknown clinical importance, classification pending). The variant was not identified in UMD (unavailable), MutDB, GeneInsight-COGR, Cosmic, ARUP Laboratories, Zhejiang Colon Cancer Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Arg466 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Gly to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000111607	SCV003927161	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-05	no assertion criteria provided	clinical testing	a variant of uncertain significance in the BRCA1 gene (p.Arg466Gly). The p.R466G variant (also known as c.1396C>G), located in coding exon 10 of the BRCA1 gene, results from a C to G substitution at nucleotide position 1396. The arginine at codon 466 is replaced by glycine, an amino acid with dissimilar properties. This alteration was identified in Moroccan and Saudi Arabian high-risk breast cancer cohorts (Tazzite A et al. Gynecol. Oncol. 2012 Jun;125:687-92; Abulkhair O et al. J Glob Oncol, 2018 08;4:1-9). This amino acid position is poorly conserved in available vertebrate species. In-silico analysis showed conflicting results. ClinVar has an entry for this variant with 6 submissions, two stars, and no conflict. This variant is not found in gnomAD genomes. Currently, the pathogenicity of this variant is not clear. Therefore, it is classified as variant of uncertain significance. Pathogenic/likely pathogenic mutations cause hereditary breast/ovarian cancer syndrome (HBOS).