Submissions for variant NM_000059.4(BRCA2):c.3852T>G (p.Ser1284Arg)

gnomAD frequency: 0.00001  dbSNP: rs777895333

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479311	SCV000568052	uncertain significance	not provided	2016-06-08	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.3852T>G at the cDNA level, p.Ser1284Arg (S1284R) at the protein level, and results in the change of a Serine to an Arginine (AGT>AGG). Using alternate nomenclature, this variant would be defined as BRCA2 4080T>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ser1284Arg was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Ser1284Arg occurs at a position that is not conserved and is located within the RAD51 interaction domain (Roy 2012). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Ser1284Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000570596	SCV000668683	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-03	criteria provided, single submitter	clinical testing	The p.S1284R variant (also known as c.3852T>G), located in coding exon 10 of the BRCA2 gene, results from a T to G substitution at nucleotide position 3852. The serine at codon 1284 is replaced by arginine, an amino acid with dissimilar 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	RCV000570596	SCV001341314	uncertain significance	Hereditary cancer-predisposing syndrome	2019-11-12	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 1284 of the BRCA2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold ≤0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/199436 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	RCV001217942	SCV001389805	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-08-09	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: 419881). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is present in population databases (rs777895333, gnomAD 0.004%). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 1284 of the BRCA2 protein (p.Ser1284Arg).
University of Washington Department of Laboratory Medicine, University of Washington	RCV000570596	SCV003846920	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).