ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5288G>T (p.Gly1763Val) (rs80357007)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048910 SCV000076923 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-07-26 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 1763 of the BRCA1 protein (p.Gly1763Val). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and valine. 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 disease. ClinVar contains an entry for this variant (Variation ID: 55507). An experimental study has shown that this missense change affects BRCA1 transcriptional activity, phospho-peptide binding specificity, and structural stability in vitro (PMID: 20516115). 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 RCV000212199 SCV000210211 uncertain significance not provided 2017-07-03 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5288G>T at the cDNA level, p.Gly1763Val (G1763V) at the protein level, and results in the change of a Glycine to a Valine (GGG>GTG). This variant has been identified in at least one individual with breast cancer (Judkins 2005). Functional studies have shown that this variant exhibits compromised phosphopeptide binding activity and specificity, mild protein folding defects, and reduced transcriptional activity compared to wild type (Lee 2010). BRCA1 Gly1763Val was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glycine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Gly1763Val occurs at a position that is conserved across species and is located in the BRCT 2 domain and a region known to interact with multiple other proteins (Paul 2014, UniProt). 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 Gly1763Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508603 SCV000605913 uncertain significance not specified 2017-01-24 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112603 SCV000145440 uncertain significance Breast-ovarian cancer, familial 1 2004-11-25 no assertion criteria provided clinical testing

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