Submissions for variant NM_007294.4(BRCA1):c.3974G>A (p.Arg1325Lys)

dbSNP: rs921253348

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484697	SCV000567037	uncertain significance	not provided	2017-12-01	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.3974G>A at the cDNA level, p.Arg1325Lys (R1325K) at the protein level, and results in the change of an Arginine to a Lysine (AGG>AAG). Using alternate nomenclature, this variant would be defined as BRCA1 4093G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Arg1325Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Lysine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Arg1325Lys occurs at a position that is not conserved and is located in the SCD domain and a region known to interact with multiple proteins (Narod 2004, Paul 2014). Based on currently available information, it is unclear whether BRCA1 Arg1325Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000509912	SCV000607993	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-30	criteria provided, single submitter	clinical testing	The p.R1325K variant (also known as c.3974G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 3974. The arginine at codon 1325 is replaced by lysine, an amino acid with highly similar properties. This variant was detected in a cohort of 3984 unselected Chinese breast cancer patients (Yao L et al. J Hum Genet, 2022 Nov;67:639-642). This amino acid position is poorly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000808684	SCV000948799	likely benign	Hereditary breast ovarian cancer syndrome	2024-09-10	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000509912	SCV003849299	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).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003321630	SCV004026770	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484697	SCV004219384	uncertain significance	not provided	2023-08-22	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 32803532 (2020), 35864222 (2022)) and gallbladder cancer (PMID: 36969051 (2023)). This variant has also been reported in unaffected individuals (PMID: 32467295 (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.