Submissions for variant NM_007294.4(BRCA1):c.1336A>G (p.Arg446Gly)

gnomAD frequency: 0.00001  dbSNP: rs587781715

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129893	SCV000184710	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-14	criteria provided, single submitter	clinical testing	The p.R446G variant (also known as c.1336A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 1336. The arginine at codon 446 is replaced by glycine, an amino acid with dissimilar properties. 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.
PreventionGenetics, part of Exact Sciences	RCV000679680	SCV000806893	uncertain significance	not provided	2017-01-10	criteria provided, single submitter	clinical testing
Invitae	RCV000695651	SCV000824163	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-11	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 446 of the BRCA1 protein (p.Arg446Gly). This variant is present in population databases (rs587781715, gnomAD 0.008%). 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: 141392). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679680	SCV001470367	uncertain significance	not provided	2020-04-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129893	SCV001736472	uncertain significance	Hereditary cancer-predisposing syndrome	2020-08-24	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 446 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/282348 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.
GeneDx	RCV000679680	SCV002757456	uncertain significance	not provided	2022-05-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 1455A>G; This variant is associated with the following publications: (PMID: 10426999, 20215511, 15343273, 9788437, 9926942, 9582019)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129893	SCV003846003	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.	RCV003335117	SCV004043177	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-05	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].