Submissions for variant NM_000059.4(BRCA2):c.2698A>C (p.Asn900His)

dbSNP: rs55736268

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000548310	SCV000635241	uncertain significance	Hereditary breast ovarian cancer syndrome	2017-06-26	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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with BRCA2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with histidine at codon 900 of the BRCA2 protein (p.Asn900His). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and histidine.
Ambry Genetics	RCV000568709	SCV000673088	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-15	criteria provided, single submitter	clinical testing	The p.N900H variant (also known as c.2698A>C), located in coding exon 10 of the BRCA2 gene, results from an A to C substitution at nucleotide position 2698. The asparagine at codon 900 is replaced by histidine, an amino acid with similar properties. 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	RCV000568709	SCV001352572	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-28	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with histidine at codon 900 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000568709	SCV003850077	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).