ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5432A>G (p.Gln1811Arg) (rs80357040)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195396 SCV000077006 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-05-31 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 1811 of the BRCA1 protein (p.Gln1811Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033) and the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 55578). Experimental studies in human cell line and yeast systems have shown that this missense change results in compromised transcriptional activation activity, and a protein folding defect by protease sensitivity analysis (PMID: 20516115, 12496477). 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.
GeneDx RCV000048993 SCV000210220 uncertain significance not provided 2016-11-01 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5432A>G at the cDNA level, p.Gln1811Arg (Q1811R) at the protein level, and results in the change of a Glutamine to an Arginine (CAG>CGG). Using alternate nomenclature, this variant has been previously published as BRCA1 5551A>G. This variant has been reported as an uncertain variant based on varying results from functional studies by Lee et al. (2010). BRCA1 Gln1811Arg 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 Glutamine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Gln1811Arg occurs at a position that is conserved in mammals and is located in the BRCT 2 domain and a region known to interact with multiple other proteins (Narod 2004, UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA1 Gln1811Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000165979 SCV000216737 uncertain significance Hereditary cancer-predisposing syndrome 2015-04-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Sharing Clinical Reports Project (SCRP) RCV000077623 SCV000109426 uncertain significance Breast-ovarian cancer, familial 1 2012-06-05 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077623 SCV000145513 uncertain significance Breast-ovarian cancer, familial 1 1998-11-30 no assertion criteria provided clinical testing

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