ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2518A>T (p.Ser840Cys) (rs377475866)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000509761 SCV000608210 uncertain significance Hereditary cancer-predisposing syndrome 2016-12-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000509761 SCV000683040 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-19 criteria provided, single submitter clinical testing
Counsyl RCV000077522 SCV000489620 uncertain significance Breast-ovarian cancer, familial 1 2016-11-03 criteria provided, single submitter clinical testing
GeneDx RCV000074573 SCV000108658 uncertain significance not specified 2017-05-31 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2518A>T at the cDNA level, p.Ser840Cys (S840C) 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 2637A>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Ser840Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating 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 Ser840Cys occurs at a position that is not conserved and is located in the DNA binding domain (Narod 2004). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA1 Ser840Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000195551 SCV000254961 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-25 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 840 of the BRCA1 protein (p.Ser840Cys). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is present in population databases (rs377475866, ExAC <0.01%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 21120943, 20104584). ClinVar contains an entry for this variant (Variation ID: 89056). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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) RCV000077522 SCV000109323 likely benign Breast-ovarian cancer, familial 1 2012-10-09 no assertion criteria provided clinical testing

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