Submissions for variant NM_000059.4(BRCA2):c.3245A>G (p.Lys1082Arg)

gnomAD frequency: 0.00001  dbSNP: rs80358569

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587691	SCV000210311	uncertain significance	not provided	2016-08-03	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.3245A>G at the cDNA level, p.Lys1082Arg (K1082R) 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 3473A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Lys1082Arg 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 Lys1082Arg occurs at a position that is not conserved and is located in the RAD51 binding domain (Roy 2012). 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 Lys1082Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587691	SCV000296508	uncertain significance	not provided	2023-01-18	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0000084 (2/236710 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with breast and/or ovarian cancer (PMID: 31825140 (2019)). 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. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on BRCA2 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites . Based on the available information, we are unable to determine the clinical significance of this variant.
Ambry Genetics	RCV000569193	SCV000666049	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-19	criteria provided, single submitter	clinical testing	The p.K1082R variant (also known as c.3245A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 3245. The lysine at codon 1082 is replaced by arginine, an amino acid with highly similar properties. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488363	SCV000694682	uncertain significance	not specified	2023-12-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3245A>G (p.Lys1082Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-06 in 236710 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3245A>G has been reported in the literature in individuals affected with breast and/or ovarian cancer without strong evidence of causality (Gao_2020, de Oliveira_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31825140, 35534704). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=8) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000113150	SCV000786494	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-05-14	criteria provided, single submitter	clinical testing
Mendelics	RCV000113150	SCV001139059	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001361625	SCV001557604	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-23	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 1082 of the BRCA2 protein (p.Lys1082Arg). This variant is present in population databases (rs80358569, gnomAD 0.003%). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 31825140, 35534704). ClinVar contains an entry for this variant (Variation ID: 51431). 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 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.
Color Diagnostics, LLC DBA Color Health	RCV000569193	SCV001735095	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-01	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 1082 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 been reported in an individual affected with breast or ovarian cancer (PMID: 31825140). This variant has been identified in 2/236710 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.
Sema4, Sema4	RCV000569193	SCV002533775	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-23	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000569193	SCV003851799	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	RCV004803156	SCV004845133	uncertain significance	BRCA2-related cancer predisposition	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 1082 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 been reported in an individual affected with breast or ovarian cancer (PMID: 31825140). This variant has been identified in 2/236710 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113150	SCV000146195	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing