Submissions for variant NM_000059.4(BRCA2):c.6301A>C (p.Asn2101His)

dbSNP: rs1430866716

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000565803	SCV000668576	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-25	criteria provided, single submitter	clinical testing	The p.N2101H variant (also known as c.6301A>C), located in coding exon 10 of the BRCA2 gene, results from an A to C substitution at nucleotide position 6301. The asparagine at codon 2101 is replaced by histidine, an amino acid with similar properties. In one study of 36 Tunisian breast cancer patients who had at least one first-degree relative with breast and/or ovarian cancer, this variant was seen at a frequency of 3%, and was reported as a polymorphism (Troudi W et al. J. Hum. Genet. 2007; 52(11):915-20). 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	RCV000565803	SCV001358481	uncertain significance	Hereditary cancer-predisposing syndrome	2019-03-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001208948	SCV001380364	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-04-09	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: 482986). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 17922257). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 2101 of the BRCA2 protein (p.Asn2101His).
University of Washington Department of Laboratory Medicine, University of Washington	RCV000565803	SCV003852406	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	RCV004802225	SCV005424525	uncertain significance	BRCA2-related cancer predisposition	2024-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with histidine at codon 2101 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals with a personal or family history of breast or ovarian cancer (PMID: 17922257). This variant has been identified in 1/243214 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.