Submissions for variant NM_000059.4(BRCA2):c.4088A>G (p.Asn1363Ser)

gnomAD frequency: 0.00001  dbSNP: rs1165204072

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000547329	SCV000635333	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-01-03	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 462322). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1363 of the BRCA2 protein (p.Asn1363Ser). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. 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.
Color Diagnostics, LLC DBA Color Health	RCV000581950	SCV000688847	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-31	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at 1363 codon 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 been reported in an unaffected individual (PMID: 33471991) and in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.0246 and 0.8796, respectively (PMID: 31131967). This variant has been identified in 2/249440 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.
Ambry Genetics	RCV000581950	SCV002632662	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-24	criteria provided, single submitter	clinical testing	The p.N1363S variant (also known as c.4088A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 4088. The asparagine at codon 1363 is replaced by serine, an amino acid with highly similar properties. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000581950	SCV003848669	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).
All of Us Research Program, National Institutes of Health	RCV003999059	SCV004845268	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-17	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at 1363 codon 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 been reported in an unaffected individual (PMID: 33471991) and in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.0246 and 0.8796, respectively (PMID: 31131967). This variant has been identified in 2/249440 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.
GeneDx	RCV004592567	SCV005079760	uncertain significance	not provided	2023-11-07	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 4316A>G; This variant is associated with the following publications: (PMID: 29884841, 32377563, 31131967)