Submissions for variant NM_000059.4(BRCA2):c.367A>G (p.Lys123Glu)

dbSNP: rs876658305

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222230	SCV000273351	uncertain significance	Hereditary cancer-predisposing syndrome	2015-01-06	criteria provided, single submitter	clinical testing	The p.K123E variant (also known as c.367A>G and 595A>G), located in coding exon 3 of the BRCA2 gene, results from an A to G substitution at nucleotide position 367. The lysine at codon 123 is replaced by glutamic acid, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6502 samples (13004 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 105,000 alleles tested) in our clinical cohort. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be benign by PolyPhen but deleterious by SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.K123E remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853506	SCV002123051	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-06-30	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). 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: 229965). 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. 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. This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 123 of the BRCA2 protein (p.Lys123Glu).
All of Us Research Program, National Institutes of Health	RCV003997787	SCV004846766	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-28	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 123 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 not been reported in individuals affected with hereditary cancer in the literature. 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.