Submissions for variant NM_000059.4(BRCA2):c.5117A>C (p.Asn1706Thr)

dbSNP: rs730881536

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160082	SCV000210345	uncertain significance	not provided	2017-06-01	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.5117A>C at the cDNA level, p.Asn1706Thr (N1706T) at the protein level, and results in the change of an Asparagine to a Threonine (AAT>ACT). Using alternate nomenclature, this variant would be defined as BRCA2 5345A>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asn1706Thr was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Asparagine and Threonine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Asn1706Thr occurs at a position that is not conserved and is located in the binding regions of RAD51 and POLH (Roy 2012, Buisson 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Asn1706Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000568700	SCV000668837	uncertain significance	Hereditary cancer-predisposing syndrome	2017-08-03	criteria provided, single submitter	clinical testing	The p.N1706T variant (also known as c.5117A>C), located in coding exon 10 of the BRCA2 gene, results from an A to C substitution at nucleotide position 5117. The asparagine at codon 1706 is replaced by threonine, an amino acid with similar properties. This amino acid position is 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.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000607894	SCV000744463	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Invitae	RCV001058918	SCV001223517	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-12-24	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: 182214). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is present in population databases (rs730881536, gnomAD 0.0009%). This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 1706 of the BRCA2 protein (p.Asn1706Thr).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160082	SCV002774492	uncertain significance	not provided	2021-06-26	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000568700	SCV003847005	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	RCV000607894	SCV004845770	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with threonine at codon 1706 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 1 individual affected with ovarian cancer and in 2 unaffected individuals (PMID: 29936257, 33471991; Leiden Open Variation Database DB-ID BRCA2_001901). This variant has also been reported in individuals affected with breast cancer in the Leiden Open-source Variation Database (PMID: 21520333). This variant has been identified in 1/231046 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000607894	SCV000733261	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000160082	SCV001905824	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000160082	SCV001956234	likely benign	not provided		no assertion criteria provided	clinical testing