ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1834A>G (p.Arg612Gly) (rs80357245)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047605 SCV000075618 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-11 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 2017-08-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
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 RCV000221996 SCV000688349 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-02 criteria provided, single submitter clinical testing
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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