Submissions for variant NM_000059.4(BRCA2):c.6037A>G (p.Lys2013Glu)

gnomAD frequency: 0.00001  dbSNP: rs80358840

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044826	SCV000072839	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-11-06	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 2013 of the BRCA2 protein (p.Lys2013Glu). This variant is present in population databases (rs80358840, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 19491284). ClinVar contains an entry for this variant (Variation ID: 51995). 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.
Ambry Genetics	RCV000162633	SCV000213069	likely benign	Hereditary cancer-predisposing syndrome	2021-12-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000162633	SCV000906923	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-18	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 2013 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 two individuals affected with breast or ovarian cancer (PMID: 19491284, 32438681). This variant has been identified in 1/250808 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174723	SCV001338000	uncertain significance	not specified	2020-01-06	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6037A>G (p.Lys2013Glu) 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 4e-06 in 250808 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6037A>G has been reported in the literature in individuals affected with Breast Cancer (Haffty_2009). This report however, does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000162633	SCV003850875	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	RCV000083121	SCV004846686	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 2013 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 two individuals affected with breast or ovarian cancer (PMID: 19491284, 32438681). This variant has been identified in 1/250808 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	RCV004998152	SCV005624481	uncertain significance	not provided	2024-02-20	criteria provided, single submitter	clinical testing	The BRCA2 c.6037A>G (p.Lys2013Glu) variant has been reported in the published literature in individuals affected with breast cancer (PMIDs: 32438681 (2020), 19491284 (2009)). In addition, 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)). The frequency of this variant in the general population, 0.0000088 (1/113394 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.
Sharing Clinical Reports Project (SCRP)	RCV000083121	SCV000115195	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2011-10-21	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083121	SCV000146754	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing