Submissions for variant NM_000059.4(BRCA2):c.4237A>G (p.Lys1413Glu)

dbSNP: rs876661198

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000219793	SCV000279768	uncertain significance	not provided	2015-12-30	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.4237A>G at the cDNA level, p.Lys1413Glu (K1413E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). Using alternate nomenclature, this variant would be defined as BRCA2 4465A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Lys1413Glu 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 Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Lys1413Glu occurs at a position that is not conserved and is located in the RAD51 binding domain and the region of interaction with POLH (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 Lys1413Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000567611	SCV000668542	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-10	criteria provided, single submitter	clinical testing	The p.K1413E variant (also known as c.4237A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 4237. The lysine at codon 1413 is replaced by glutamic acid, an amino acid with 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.
Color Diagnostics, LLC DBA Color Health	RCV000567611	SCV000688859	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-18	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 1413 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 individuals with a personal or family history of breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008178, 37415649). This variant has not been identified 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.
Mendelics	RCV000989026	SCV001139085	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV000709310	SCV001387960	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-08-24	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). 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. 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. ClinVar contains an entry for this variant (Variation ID: 234751). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 1413 of the BRCA2 protein (p.Lys1413Glu).
University of Washington Department of Laboratory Medicine, University of Washington	RCV000567611	SCV003848783	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).
PreventionGenetics, part of Exact Sciences	RCV004532817	SCV004106335	uncertain significance	BRCA2-related disorder	2023-06-23	criteria provided, single submitter	clinical testing	The BRCA2 c.4237A>G variant is predicted to result in the amino acid substitution p.Lys1413Glu. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as variant of uncertain significance and likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/234751/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV000989026	SCV004845286	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 1413 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 individuals with a personal or family history of breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008178, 37415649). This variant has not been identified 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.