Submissions for variant NM_000059.4(BRCA2):c.5990G>A (p.Arg1997Lys)

dbSNP: rs1064793478

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586598	SCV000566226	uncertain significance	not provided	2017-09-05	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.5990G>A at the cDNA level, p.Arg1997Lys (R1997K) at the protein level, and results in the change of an Arginine to a Lysine (AGA>AAA). This variant, also known as BRCA2 6218G>A using alternate nomenclature, has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Arg1997Lys was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Lysine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Arg1997Lys occurs at a position that is not conserved and is located in the BRC7 domain and the region of interaction with RAD51 (Cole 2011, Roy 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Arg1997Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586598	SCV000694925	uncertain significance	not provided	2017-02-21	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 5990G>A (p.Arg1997Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). The variant is located in one of the BRCA repeats that is critical for binding to RAD51 (a key protein in DNA recombinational repair) and resistance to methyl methanesulphonate treatment. The variant is absent from control datasets of ExAC and gnomAD (120,488 and 251,944 chrs tested, respectively). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or cited by clinical diagnostic laboratories, nor was it evaluated for functional impact by in vivo/vitro studies. UMD reports this variant in 1 patient and classifies it as "unknown variant" as of 19/04/16. Due to the absence of clinical information and lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001302502	SCV001491715	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-03-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 1997 of the BRCA2 protein (p.Arg1997Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 418858). 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 BRCA2 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.
Ambry Genetics	RCV002356768	SCV002658766	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-27	criteria provided, single submitter	clinical testing	The p.R1997K variant (also known as c.5990G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 5990. The arginine at codon 1997 is replaced by lysine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and lysine is the reference amino acid in other 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002356768	SCV003850839	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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586598	SCV004220483	uncertain significance	not provided	2023-09-05	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported 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.