Submissions for variant NM_000059.4(BRCA2):c.6485A>G (p.Lys2162Arg)

gnomAD frequency: 0.00001  dbSNP: rs11571660

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478743	SCV000568166	uncertain significance	not provided	2016-09-22	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.6485A>G at the cDNA level, p.Lys2162Arg (K2162R) at the protein level, and results in the change of a Lysine to an Arginine (AAA>AGA). Using alternate nomenclature, this variant would be defined as BRCA2 6713A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Lys2162Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Lys2162Arg occurs at a position that is not conserved and is not located in a known functional domain (Roy 2012, UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Lys2162Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000772763	SCV000906142	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-26	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 2162 of the BRCA2 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 hereditary cancer in the literature. This variant has been identified in 3/234006 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.
Ambry Genetics	RCV000772763	SCV001187486	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-21	criteria provided, single submitter	clinical testing	The p.K2162R variant (also known as c.6485A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 6485. The lysine at codon 2162 is replaced by arginine, an amino acid with highly similar 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001203351	SCV001374512	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-18	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 2162 of the BRCA2 protein (p.Lys2162Arg). This variant is present in population databases (rs11571660, gnomAD 0.008%). 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: 419941). 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.
Molecular Endocrinology Laboratory, Christian Medical College	RCV001770369	SCV002003996	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000772763	SCV003852576	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).
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001770369	SCV003924416	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-05-17	criteria provided, single submitter	clinical testing	A variant of uncertain significance was detected in the BRCA2 gene (c.6485A>G). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 2162 of the BRCA2 protein (p.Lys2162Arg). This variant is present in population databases (rs11571660, gnomAD 0.008%). This amino acid position is not well conserved ( PhyloP=1.23) . 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: 419941) classified as uncertain significance . In silico analyses predict that this variant is unlikely to alter protein structure or function. 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003321631	SCV004027461	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001770369	SCV004844271	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-05-08	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 2162 of the BRCA2 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 hereditary cancer in the literature. This variant has been identified in 3/234006 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.