ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130620 SCV000185496 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000113466 SCV000146673 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000130620 SCV000903958 likely benign Hereditary cancer-predisposing syndrome 2016-12-19 criteria provided, single submitter clinical testing
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.
Invitae RCV000044725 SCV000072738 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-21 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 1905 of the BRCA2 protein (p.His1905Arg). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 51913). Based on a multifactorial likelihood algorithm using in silico data, this variant has been determined to have a low probability of being pathogenic (PMID: 24489791). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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