Submissions for variant NM_000059.4(BRCA2):c.1114A>G (p.Asn372Asp)

dbSNP: rs144848

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001017368	SCV001178442	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-07	criteria provided, single submitter	clinical testing	The p.N372D variant (also known as c.1114A>G), located in coding exon 9 of the BRCA2 gene, results from an A to G substitution at nucleotide position 1114. The asparagine at codon 372 is replaced by aspartic acid, 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	RCV001319297	SCV001510037	uncertain significance	Hereditary breast ovarian cancer syndrome	2020-05-21	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with aspartic acid at codon 372 of the BRCA2 protein (p.Asn372Asp). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant has not been reported in the literature in individuals with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 822206). 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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The aspartic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001017368	SCV003849842	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).