ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5143A>T (p.Ser1715Cys) (rs80357222)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129744 SCV000184550 likely pathogenic Hereditary cancer-predisposing syndrome 2017-01-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Other strong data supporting pathogenic classification,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Well-characterized mutation at same position
Breast Cancer Information Core (BIC) (BRCA1) RCV000112506 SCV000145328 uncertain significance Breast-ovarian cancer, familial 1 2002-06-20 no assertion criteria provided clinical testing
GeneDx RCV000586760 SCV000293460 uncertain significance not provided 2016-03-16 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5143A>T at the cDNA level, p.Ser1715Cys (S1715C) at the protein level, and results in the change of a Serine to a Cysteine (AGC>TGC). Using alternate nomenclature, this variant would be defined as BRCA1 5262A>T. This variant was predicted to be destabilizing to the protein due to the formation of inclusion bodies in E. coli. (Rowling 2010). However, additional in vitro functional analyses suggest that BRCA1 Ser1715Cys has only a mild impact on protein folding, normal binding activity, uncertain binding specificity, and compromised transcriptional activity (Lee 2010). BRCA1 Ser1715Cys 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 Serine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Ser1715Cys occurs at a position that is conserved in mammals and is located in the BRCT1 domain as well as 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 currently available evidence, it is unclear whether BRCA1 Ser1715Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000586760 SCV000699207 uncertain significance not provided 2017-03-15 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5143A>T (p.Ser1715Cys) variant causes a missense change involving the alteration of a conserved nucleotide. 5/5 in silico tools predict a deleterious outcome for this variant. The variant is absent from control datasets of ExAC and gnomAD (120308 and 246144 chrs tested, respectively). In the fanctional studies the variant displayed mild to moderate impact on protein folding, binding activity and specificity and significant impact on transcriptional activity (Lee, 2010; Gaboriau, 2015). This variant was predicted to be destabilizing to the protein due to the formation of inclusion bodies in E. coli, but was classified as having no effect on HDR (Gaboriau, 2015). The variant of interest been identified in at least 1 individual tested at Myriad. Due to the inconclusive functional studies and the lack of clinical information, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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