Submissions for variant NM_000059.4(BRCA2):c.10078A>G (p.Lys3360Glu)

dbSNP: rs1593202262

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000803795	SCV000943681	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-11-19	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 3360 of the BRCA2 protein (p.Lys3360Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with personal or family history of breast and/or ovarian cancer (PMID: 21120943, 31851867, 32599251, 32994724). ClinVar contains an entry for this variant (Variation ID: 648957). 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	RCV001009673	SCV001169770	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-21	criteria provided, single submitter	clinical testing	The p.K3360E variant (also known as c.10078A>G), located in coding exon 26 of the BRCA2 gene, results from an A to G substitution at nucleotide position 10078. The lysine at codon 3360 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been identified in individuals considered high risk for Hereditary Breast and/or Ovarian Cancer (Caux-Moncoutier V et al. Hum. Mutat., 2011 Mar;32:325-34; Peker Eyübolu et al. OMICS, 2020 01;24:5-15). This alteration has also been identified in an individual diagnosed with breast cancer (Alanazi M et al. Saudi J Biol Sci, 2020 Oct;27:2651-2659). This alteration was not observed in 53 unselected male breast cancer patients and was observed with an allele frequency of 0.0001 in 12,490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). 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.
Color Diagnostics, LLC DBA Color Health	RCV001009673	SCV001348942	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-21	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 3360 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 detected in at least three individuals affected with breast cancer (PMID: 32599251, 32994724; Color internal data) and two suspected hereditary breast and ovarian cancer families (PMID: 21120943, 31851867). This variant also has been reported in breast, prostate and pancreatic cancer case-control studies in which this variant was detected in one unaffected individual in each study and was absent in cancer cases (PMID: 30287823, 31214711, 32980694). 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002268293	SCV002551856	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing