ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1834A>G (p.Arg612Gly) (rs80357245)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000111696 SCV001161490 benign Breast-ovarian cancer, familial 1 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000492
Invitae RCV000047605 SCV000075618 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 612 of the BRCA1 protein (p.Arg612Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs80357245, ExAC 0.006%). This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 27125725, 26689913). However, in one of these individuals a pathogenic allele was also identified in BRCA2, which suggests that this c.1834A>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 54367). An experimental study has shown that this missense change does not impair the homology-directed repair activity of the BRCA1 protein (PMID: 26689913). 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.
Ambry Genetics RCV000221996 SCV000275535 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-14 criteria provided, single submitter clinical testing The p.R612G variant (also known as c.1834A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 1834. The arginine at codon 612 is replaced by glycine, an amino acid with dissimilar properties. Using a comparative evolutionary approach, multiple studies have predicted that this missense alteration affects protein function because it occurs at a conservative site (Fleming MA et al. Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1151-6; Burk-Herrick A et al. Mamm Genome. 2006 Mar;17(3):257-70; Ramirez CJ et al. Oncogene. 2004 Mar 4;23(9):1780-8). 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.
Counsyl RCV000111696 SCV000489573 uncertain significance Breast-ovarian cancer, familial 1 2016-10-27 criteria provided, single submitter clinical testing
GeneDx RCV000485391 SCV000568878 uncertain significance not provided 2016-08-29 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1834A>G at the cDNA level, p.Arg612Gly (R612G) at the protein level, and results in the change of an Arginine to a Glycine (AGG>GGG). Using alternate nomenclature, this variant would be defined as BRCA1 1953A>G. This variant was co-observed with a pathogenic BRCA2 variant in an individual with bilateral breast and ovarian cancer (Minucci 2016). BRCA1 Arg612Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Arg612Gly occurs at a position that is not conserved and is located within the NLS2 motif and a region known for interaction with multiple proteins (Borg 2010, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Arg612Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000221996 SCV000688349 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-12 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000485391 SCV001133500 uncertain significance not provided 2019-02-01 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001660164 SCV001878206 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Breast Cancer Information Core (BIC) (BRCA1) RCV000111696 SCV000144198 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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