ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5714A>G (p.His1905Arg) (rs80358796)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044725 SCV000072738 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130620 SCV000185496 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-14 criteria provided, single submitter clinical testing The p.H1905R variant (also known as c.5714A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 5714. The histidine at codon 1905 is replaced by arginine, an amino acid with highly similar properties. This alteration was observed in 0/7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00009 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). Authors of one study classified this variant as likely not pathogenic based on a combination of multifactorial likelihood analyses and an in vitro splicing assay and another study using four in silico prediction tools found this variant to be tolerated in all models (Whiley PJ et al. PLoS One, 2014 Jan;9:e86836; Ernst C et al. BMC Med Genomics, 2018 03;11:35). 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.
GeneDx RCV000479143 SCV000569646 uncertain significance not provided 2018-02-22 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5714A>G at the cDNA level, p.His1905Arg (H1905R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). Using alternate nomenclature, this variant would be defined as BRCA2 5942A>G. BRCA2 His1905Arg was classified as likely not pathogenic by a multifactorial likelihood analysis utilizing bioinformatic models and segregation data (Whiley 2014). BRCA2 His1905Arg was not observed in large population databases (Lek 2016). Since Histidine and Arginine share similar properties, this is considered a conservative amino acid substitution. BRCA2 His1905Arg is located in the RAD51 binding domain (Roy 2012). In silico analysis, which includes protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 His1905Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000130620 SCV000903958 likely benign Hereditary cancer-predisposing syndrome 2016-12-19 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113466 SCV000146673 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.