Submissions for variant NM_000059.4(BRCA2):c.3923A>C (p.Glu1308Ala)

dbSNP: rs2137501297

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002322310	SCV002626310	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-31	criteria provided, single submitter	clinical testing	The p.E1308A variant (also known as c.3923A>C), located in coding exon 10 of the BRCA2 gene, results from an A to C substitution at nucleotide position 3923. The glutamic acid at codon 1308 is replaced by alanine, an amino acid with dissimilar properties. This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002547685	SCV003287826	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-01-06	criteria provided, single submitter	clinical testing	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: 1050526). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 1308 of the BRCA2 protein (p.Glu1308Ala).
University of Washington Department of Laboratory Medicine, University of Washington	RCV002322310	SCV003848535	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358069	SCV001553717	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Glu1308Ala variant was not identified in the literature nor was it identified in the dbSNP, ClinVar, GeneInsight-COGR, Cosmic, MutDB, LOVD 3.0, UMD-LSDB, BIC, ARUP Laboratories, or Zhejiang University databases. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Glu1308 residue is conserved in mammals but not in more distantly related organisms. However, four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.