Submissions for variant NM_000059.4(BRCA2):c.4549A>G (p.Lys1517Glu)

dbSNP: rs730881532

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160078	SCV000210338	uncertain significance	not provided	2025-02-12	criteria provided, single submitter	clinical testing	Observed in a patient with breast cancer (PMID: 33471991); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4777A>G; This variant is associated with the following publications: (PMID: 33471991, 32377563, 29884841)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000541569	SCV000635378	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-25	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 1517 of the BRCA2 protein (p.Lys1517Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 182210). 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	RCV000575191	SCV000668549	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-04	criteria provided, single submitter	clinical testing	The p.K1517E variant (also known as c.4549A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 4549. The lysine at codon 1517 is replaced by glutamic acid, an amino acid with similar properties. This variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	RCV000575191	SCV003850600	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).
Color Diagnostics, LLC DBA Color Health	RCV000575191	SCV004362059	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-27	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 1517 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 cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008236). This variant has been identified in 1/250542 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.
All of Us Research Program, National Institutes of Health	RCV004804693	SCV005424438	uncertain significance	BRCA2-related cancer predisposition	2024-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 1517 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 cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008236). This variant has been identified in 1/250542 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.