ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4456A>T (p.Ser1486Cys) (rs397507232)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481363 SCV000572363 uncertain significance not provided 2016-11-28 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4456A>T at the cDNA level, p.Ser1486Cys (S1486C) at the protein level, and results in the change of a Serine to a Cysteine (AGT>TGT). Using alternate nomenclature, this variant would be defined as BRCA1 4575A>T. This variant has been reported to not have a negative impact on transcriptional activation in a luciferase reporter based assay and was also reported to function similarly to wild-type controls in a cisplatin sensitivity assay (Bouwman 2013, Woods 2016). BRCA1 Ser1486Cys 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 Ser1486Cys occurs at a position that is not conserved and is located within the SCD domain as well as the ATM, CHEK2, and CDK2 binding domains (Narod 2004, Clark 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Ser1486Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000570933 SCV000668511 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-07 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000637687 SCV000759157 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-09-05 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 1486 of the BRCA1 protein (p.Ser1486Cys). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is present in population databases (rs397507232, ExAC 0.01%). This variant has been not been reported in individuals affected with BRCA1-related diseases. ClinVar contains an entry for this variant (Variation ID: 37593). Experimental studies have shown that this variant does not impact transcriptional activity of the encoded protein in vitro (PMID: 28781887). 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.
Sharing Clinical Reports Project (SCRP) RCV000031174 SCV000053774 uncertain significance Breast-ovarian cancer, familial 1 2008-01-04 no assertion criteria provided clinical testing
3DMed Clinical Laboratory Inc RCV000677796 SCV000803952 uncertain significance Cancer of the pancreas 2017-03-30 no assertion criteria provided clinical testing

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