Submissions for variant NM_000059.4(BRCA2):c.2666A>G (p.Asn889Ser)

dbSNP: rs1555282782

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000509614	SCV000608146	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-03	criteria provided, single submitter	clinical testing	The p.N889S variant (also known as c.2666A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 2666. The asparagine at codon 889 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637362	SCV000758818	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 889 of the BRCA2 protein (p.Asn889Ser). This variant is not present in population databases (gnomAD no frequency). 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: 441454). 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.
Sema4, Sema4	RCV000509614	SCV002535513	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-26	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000509614	SCV003848486	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	RCV004003579	SCV004845042	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 889 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 not been identified 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV005000065	SCV005624364	uncertain significance	not provided	2023-10-16	criteria provided, single submitter	clinical testing