ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5154G>T (p.Trp1718Cys) (rs80357239)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129752 SCV000184559 likely pathogenic Hereditary cancer-predisposing syndrome 2013-09-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Moderate segregation with disease (at least 3 informative meioses) for rare diseases.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112539 SCV000145362 uncertain significance Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
GeneDx RCV000482189 SCV000572126 likely pathogenic not provided 2016-10-25 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5154G>T at the cDNA level, p.Trp1718Cys (W1718C) at the protein level, and results in the change of a Tryptophan to a Cysteine (TGG>TGT). Using alternate nomenclature, this variant would be defined as/ has been previously published as BRCA1 5273G>T. This variant has been observed in individuals with triple negative breast cancer and familial breast/ovarian cancer, and was reported to segregate with disease in a breast cancer kindred (Blay 2013, Eccles 2015, Couch 2015). Functional assays have found this variant to impact transcriptional activation and lead to protein destabilization (Williams 2003, Mirkovic 2004, Lee 2010). Additionally, this variant demonstrated cisplatin sensitivity and lack of growth rescue similar to pathogenic variants in mouse embryonic stem cells (Bouwman 2013).BRCA1 Trp1718Cys 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 Trp1718Cys occurs at a position that is conserved in mammals and is located in the first BRCT domain and a region known to interact with multiple other proteins (UniProt, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider BRCA1 Trp1718Cys to be a likely pathogenic variant.

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