ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5511G>C (p.Trp1837Cys) (rs80356914)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483084 SCV000570380 uncertain significance not provided 2016-05-17 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5511G>C at the cDNA level, p.Trp1837Cys (W1837C) at the protein level, and results in the change of a Tryptophan to a Cysteine (TGG>TGC). Using alternate nomenclature, this variant would be defined as BRCA1 5630G>C. Functional studies suggest that this variant results in compromised binding activity, specificity, transcriptional activity, and a severe folding defect as compared to wild type (Lee 2010). BRCA1 Trp1837Cys 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 Tryptophan and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Trp1837Cys occurs at a position that is conserved across species and is located in BRCT2 domain as well as a region known to interact with multiple proteins (Narod 2004, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Despite some evidence suggesting pathogenicity, there is not currently enough evidence to determine whether BRCA1 Trp1837Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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