Submissions for variant NM_000059.4(BRCA2):c.3368G>A (p.Ser1123Asn)

dbSNP: rs1555283202

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000572509	SCV000668852	uncertain significance	Hereditary cancer-predisposing syndrome	2017-08-29	criteria provided, single submitter	clinical testing	The p.S1123N variant (also known as c.3368G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 3368. The serine at codon 1123 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is highly 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	RCV001054565	SCV001218885	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-04-29	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 483133). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with asparagine at codon 1123 of the BRCA2 protein (p.Ser1123Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000572509	SCV003851903	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).
GeneDx	RCV004773009	SCV005385197	uncertain significance	not provided	2024-01-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 3596G>A
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358197	SCV001553870	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The BRCA2 p.Ser1123Asn variant was not identified in the literature nor was it identified in the dbSNP, LOVD 3.0, or UMD-LSDB. The variant was only identified in ClinVar (classified as uncertain significance by Ambry Genetics).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.Ser1123 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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.