Submissions for variant NM_007294.4(BRCA1):c.2840A>G (p.Lys947Arg)

dbSNP: rs778118145

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000568879	SCV000665863	uncertain significance	Hereditary cancer-predisposing syndrome	2016-07-07	criteria provided, single submitter	clinical testing	The p.K947R variant (also known as c.2840A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 2840. The lysine at codon 947 is replaced by arginine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.0003% (greater than 300000 alleles tested) in our clinical cohort. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000792546	SCV000931850	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-29	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 947 of the BRCA1 protein (p.Lys947Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 481455). 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 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.
Color Diagnostics, LLC DBA Color Health	RCV000568879	SCV001359692	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-31	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 947 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 not been reported in individuals affected with BRCA1-related disorders in the literature. This variant has been identified in 1/251322 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000568879	SCV003849312	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).
All of Us Research Program, National Institutes of Health	RCV004802208	SCV004815646	uncertain significance	BRCA1-related cancer predisposition	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 947 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 not been reported in individuals affected with BRCA1-related disorders in the literature. This variant has been identified in 1/251322 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV005000262	SCV005626055	uncertain significance	not provided	2024-04-10	criteria provided, single submitter	clinical testing	The BRCA1 c.2840A>G (p.Lys947Arg) variant has been reported in the published literature to be located in a region of the BRCA1 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)) and is predicted to be benign based on multifactorial likelihood analysis (PMID: 31853058 (2020)). To the best of our knowledge, this variant has not been reported in individuals with BRCA1-related disorders. The frequency of this variant in the general population, 0.000004 (1/251322 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.