Submissions for variant NM_007294.4(BRCA1):c.1270G>C (p.Gly424Arg)

dbSNP: rs763051683

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482955	SCV000566407	uncertain significance	not provided	2017-10-12	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.1270G>C at the cDNA level, p.Gly424Arg (G424R) at the protein level, and results in the change of a Glycine to an Arginine (GGT>CGT). Using alternate nomenclature, this variant would be defined as BRCA1 1389G>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Gly424Arg was not observed in large population cohorts (Lek 2016). Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Gly424Arg occurs at a position that is not conserved and is located in a region known to interact with multiple proteins (Paul 2014). Protein based in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function, while splicing models predict that this variant may strengthen the cryptic splice acceptor site and possibly cause abnormal splicing. Based on currently available evidence, it is unclear whether BRCA1 Gly424Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000561054	SCV000660985	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-15	criteria provided, single submitter	clinical testing	The p.G424R variant (also known as c.1270G>C), located in coding exon 9 of the BRCA1 gene, results from a G to C substitution at nucleotide position 1270. The glycine at codon 424 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690584	SCV000818274	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-13	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 424 of the BRCA1 protein (p.Gly424Arg). 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: 418958). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt BRCA1 protein function with a positive predictive value of 80%. 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	RCV000561054	SCV003846054	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.	RCV004023116	SCV004931801	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2024-01-29	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].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482955	SCV005626001	uncertain significance	not provided	2024-08-26	criteria provided, single submitter	clinical testing	The BRCA1 c.1270G>C (p.Gly424Arg) variant has been reported in the published literature in an individual undergoing multigene panel testing for hereditary cancer (PMID: 31853058 (2020)), and described to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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.