Submissions for variant NM_000059.4(BRCA2):c.8569G>T (p.Ala2857Ser)

dbSNP: rs730881565

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160153	SCV000210476	uncertain significance	not provided	2014-01-27	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.8569G>T at the cDNA level, p.Ala2857Ser (A2857S) at the protein level, and results in the change of an Alanine to a Serine (GCC>TCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ala2857Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative substitution in which a neutral non-polar amino acid is replaced with a neutral polar one, altering a position that is highly variable throughout evolution and is located in the DNA binding domain (Borg 2010). In silico analyses predict this variant to have a benign effect on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Ala2857Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000216821	SCV000274400	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-16	criteria provided, single submitter	clinical testing	The p.A2857S variant (also known as c.8569G>T), located in coding exon 19 of the BRCA2 gene, results from a G to T substitution at nucleotide position 8569. The alanine at codon 2857 is replaced by serine, an amino acid with similar properties. 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	RCV000216821	SCV001734898	uncertain significance	Hereditary cancer-predisposing syndrome	2021-01-26	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 2857 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 been identified in 1/251218 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002304201	SCV002591592	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-04-25	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2857 of the BRCA2 protein (p.Ala2857Ser). This variant is present in population databases (rs730881565, gnomAD 0.003%). 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: 182252). 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 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.