ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2798G>C (p.Gly933Ala) (rs80356941)

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Total submissions: 8
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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) RCV000989896 SCV001161496 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 = 0.00015
Ambry Genetics RCV000216171 SCV000277632 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-10 criteria provided, single submitter clinical testing The p.G933A variant (also known as c.2798G>C), located in coding exon 9 of the BRCA1 gene, results from a G to C substitution at nucleotide position 2798. The glycine at codon 933 is replaced by alanine, an amino acid with similar properties. 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 RCV000486989 SCV000572402 uncertain significance not provided 2017-01-30 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2798G>C at the cDNA level, p.Gly933Ala (G933A) at the protein level, and results in the change of a Glycine to an Alanine (GGT>GCT). Using alternate nomenclature, this variant would be defined as BRCA1 2917G>C. This variant was observed in at least one family with breast and/or ovarian cancer (Lu 2012). BRCA1 Gly933Ala 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 Glycine and Alanine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Gly933Ala occurs at a position that is not conserved and is located within the DNA binding domain and in a region that binds RAD51 (Chen 1998, Narod 2004). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Gly933Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000548703 SCV000635865 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-09-09 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 933 of the BRCA1 protein (p.Gly933Ala). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 233288). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a low probability of being pathogenic (PMID: 31131967). 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.
Mendelics RCV000548703 SCV000839267 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000989896 SCV001140569 uncertain significance Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV000216171 SCV001339691 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-19 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000486989 SCV001716306 uncertain significance not provided 2020-11-30 criteria provided, single submitter clinical testing

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