Submissions for variant NM_000059.4(BRCA2):c.4195T>C (p.Cys1399Arg)

dbSNP: rs730881530

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160074	SCV000210331	uncertain significance	not provided	2014-08-08	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.4195T>C at the cDNA level, p.Cys1399Arg (C1399R) at the protein level, and results in the change of a Cysteine to an Arginine (TGT>CGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Cys1399Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Cysteine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Cys1399Arg occurs at a position that is variable across vertebrates and is located within a region that interacts with POLH and RAD51 (UniProt, Roy 2012). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Cys1399Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000561378	SCV000661320	likely benign	Hereditary cancer-predisposing syndrome	2023-11-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001204737	SCV001375957	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-04-12	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). 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: 182207). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1399 of the BRCA2 protein (p.Cys1399Arg).
University of Washington Department of Laboratory Medicine, University of Washington	RCV000561378	SCV003848757	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).